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Advances in B-cell Precursor Acute Lymphoblastic Leukemia Genomics

Schwab, Claire; Harrison, Christine J.

doi: 10.1097/HS9.0000000000000053
Review Article

In childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), cytogenetic abnormalities remain important diagnostic and prognostic tools. A number of well-established abnormalities are routinely used in risk stratification for treatment. These include high hyperdiploidy and ETV6-RUNX1 fusion, classified as good risk, while Philadelphia chromosome (Ph) positive ALL and rearrangements of the KMT2A (MLL) gene define poor risk. A poor risk subgroup of intrachromosomal amplification of chromosome 21 (iAMP21-ALL) has been described, in which intensification of therapy has greatly improved outcome.

Until recently, no consistent molecular features were defined in around 30% of BCP-ALL (known as B-other-ALL). Recent studies are classifying them into distinct subgroups, some with clear potential for novel therapeutic approaches. For example, in 1 poor risk subtype, known as Ph-like/BCR-ABL1-like ALL, approximately 10% have rearrangements of ABL-class tyrosine kinases: including ABL1, ABL2, PDGFRB, PDGFRA, and CSF1R. Notably, they show a poor response to standard chemotherapy, while they respond to treatment with tyrosine kinase inhibitors, such as imatinib. In other Ph-like-ALL patients, deregulation of the cytokine receptor, CRLF2, and JAK2 rearrangements lead to activation of the JAK-STAT signaling pathway, implicating a specific role for JAK inhibitors in their treatment. Other novel subgroups within B-other-ALL are defined by the IGH-DUX4 translocation, related to deletions of the ERG gene and a good outcome, while fusions involving ZNF384, MEF2D, and intragenic PAX5 amplification (PAX5 AMP) are linked to a poor outcome. Continued genetic screening will eventually lead to complete genomic classification of BCP-ALL and define more molecular targets for less toxic therapies.

Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, United Kingdom

Correspondence: Christine J. Harrison (. e-mail: christine.harrison@newcastle.ac.uk).

Citation: Schwab C, Harrison CJ. Advances in B-cell Precursor Acute Lymphoblastic Leukemia Genomics. HemaSphere, 2018;2:4. http://dx.doi.org/10.1097/HS9.0000000000000053

Received 14 February, 2018

Revised 13 April, 2018

Accepted 20 April, 2018

Funding/support: Bloodwise, UK.

Disclosure: The authors have indicated they have no potential conflicts of interest to disclose.

This is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. http://creativecommons.org/licenses/by-nd/4.0

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INTRODUCTION

Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood, with an annual incidence of 35 per million children aged 0 to 14 years.1 There is a peak incidence between the ages of 2 to 5 years, with more than 75% of cases occurring in this age group.2 More than 80% are B-cell precursor ALL (BCP-ALL), while the remainder comprise T-lineage ALL. BCP-ALL is generally associated with a good outcome in children, with cure rates approaching 90% for patients treated on modern risk-adjusted protocols.3 Despite these improvements in treatment response, ALL remains one of the leading causes of cancer-related mortality in children, with patients succumbing to relapse or treatment-related death.2 Survivors of ALL also endure long-term effects of toxic chemotherapy.4 It is, therefore, important to continue to identify those patients who require less intensive therapy to achieve cure and to identify new targets for the development of novel, less toxic therapeutic agents.

The important risk factors used in stratification for treatment include age, white blood cell count, indicators of the National Cancer Institute risk status, treatment response, measured by the level of minimal residual disease (MRD), and cytogenetics. Over the past 4 decades, cytogenetics has proved to be a powerful tool in understanding the genetic basis of ALL, while providing essential diagnostic and prognostic information. A number of the well-established chromosomal abnormalities are routinely incorporated into clinical trials and used in risk stratification for treatment, which has significantly contributed to the improved outcomes seen in childhood ALL today. Recent innovative approaches have led to the identification of many novel genetic changes shown to impact on outcome. In this article, historical and new genetic subtypes will be reviewed in relation to their biological and clinical significance, within the context of modern therapeutic approaches.

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CYTOGENETICS OF BCP-ALL: A HISTORICAL PERSPECTIVE

Established chromosomal abnormalities of prognostic relevance

Results from cytogenetic studies over the past 45 years have classified the majority of BCP-ALL according to their primary cytogenetic abnormalities (Fig. 1).5 Trial-based studies showed that these cytogenetic subgroups correlated with age and were strongly linked to outcome.6 For example, the translocation, t(12;21)(p13;q22)/ETV6-RUNX1 fusion, and high hyperdiploidy (51–65 chromosomes) occur predominantly in children, together they account for more than 50% of childhood BCP-ALL, and are associated with a good prognosis. On the contrary, translocations involving KMT2A (formerly MLL) at 11q23 are associated with a poor prognosis. They occur in approximately 2% of childhood and adult BCP-ALL, with an elevated incidence of 85% in infants with ALL. A number of rearrangements involving the NUTM1 gene are also prevalent in infants, in particular among those who lack KMT2A rearrangements.7,8

Figure 1

Figure 1

The translocation, t(9;22)(q34;q11)/BCR-ABL1 fusion, is also a marker of poor outcome, with incidence increasing with age from about 2% in children to around 25% in younger adults. Near-haploidy (<30 chromosomes) and low hypodiploidy (30–39 chromosomes) remain linked to poor survival across the range of modern contemporary treatment protocols. The translocation, t(1;19)(q23;p13)/TCF3-PBX1 fusion, accounts for approximately 4% of BCP-ALL. Originally classified as poor risk, outcome for these patients has improved significantly on modern therapeutic regimens. However, prognosis of the rare variant translocation, also involving TCF3, t(17;19)(q22;p13)/TCF3-HLF fusion, remains dismal on all treatment protocols. For many years, these abnormalities have provided the basic gold standard genetic classification of BCP-ALL worldwide. Classical techniques of cytogenetics, fluorescence in situ hybridization (FISH), and reverse transcription polymerase chain reaction (RT-PCR) have facilitated robust and accurate detection for streamlined and universally applied risk stratification.

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ALL with intrachromosomal amplification of chromosome 21

More recently, intrachromosomal amplification of chromosome 21-ALL (iAMP21-ALL) has been included in the risk stratification algorithm as a distinct entity of BCP-ALL recognized by World Health Organization (WHO).9 These patients account for approximately 2% of BCP-ALL, they present at an older age (median 9 years) and usually with a low white cell count.10 The iAMP21 chromosome is a grossly abnormal copy of chromosome 21, comprising multiple regions of gain, amplification, inversion, and deletion. It was first identified from routine FISH screening for the presence of the ETV6-RUNX1 fusion. In a subset of patients without the ETV6-RUNX1 fusion, multiple copies of the RUNX1 gene, clustered on a single abnormal chromosome, were observed.11 Although the chromosome morphology and patterns of loss and gain varied markedly between patients (Fig. 2A), genomic profiling identified a common region of amplification.12 The majority of patients also have deletions of the telomeric end of chromosome 21. Whole genome sequencing demonstrated that the iAMP21 chromosome is generated over several cell divisions, involving multiple mutational processes including: breakage-fusion-bridge cycles following telomere attrition, chromothripsis, and large-scale chromosomal duplications.13

Figure 2

Figure 2

The amplified region usually includes the RUNX1 gene, so FISH using probes to target RUNX1 remains a reliable detection method for iAMP21-ALL. Currently, the internationally accepted definition of iAMP21-ALL is 3 or more extra copies of RUNX1 on a single abnormal chromosome 21 (a total of 5 or more RUNX1 signals per cell) (Fig. 2B).14 For laboratories unable to perform FISH, determination of copy number, using copy number arrays (Fig. 2C) or Multiplex Ligation-dependent Probe Amplification, with specifically designed kits containing probes targeting chromosome 21, provide alternative methods to identify iAMP21-ALL.15

Accurate diagnosis of iAMP21-ALL is important in the clinical setting, as patients have a high relapse rate when treated on standard therapy.16 Data from the UK ALL97 trial showed that patients with iAMP21-ALL had a 10-year event-free survival (EFS) of only 15%. However, the overall survival (OS) was significantly higher at 71%, indicating that these patients responded well to more intensive postrelapse therapy.6,17 Based on these observations, children with iAMP21-ALL treated on the subsequent trial, UKALL2003, were treated with intensive chemotherapy from the time of diagnosis. This stratification resulted in significant improvements in 5-year EFS (from 29% to 78%), relapse risk (reduced from 70% to 16%), and OS (from 67% to 89%).18 These findings were validated within the Children's Oncology Group (COG), which showed similar results in treatment trials in the United States.19

Genomic and copy number profiling have shown that patients with iAMP21-ALL also harbor secondary genetic abnormalities, which may be amenable to therapy with targeted agents. Targeted sequencing showed that approximately 60% of iAMP21-ALL patients had mutations in genes within the RAS signaling pathway. iAMP21-ALL cells in vitro showed reduced viability in response to treatment with the RAS pathway inhibitor, selumetinib.20 In addition, approximately 20% of iAMP21-ALL patients harbor the P2RY8-CRLF2 fusion. This fusion leads to deregulated expression of the cytokine receptor, CRLF2,21 and activation of the JAK-STAT signaling pathway,22 suggesting that aberrant JAK-STAT signaling is important in iAMP21-ALL leukemogenesis. The report of a subset of iAMP21-ALL patients with deletions of SH2B3,23 an abnormality which also leads to activation of the JAK-STAT pathway in BCP-ALL,24,25 has further highlighted the involvement of this pathway and the potential role of JAK inhibitors in treatment of patients with iAMP21-ALL. Ongoing studies to decipher the genomic complexity of the iAMP21 chromosome will identify genes on chromosome 21 as potential targets for novel therapies, to reduce the toxicities of their current high-risk treatment.

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NOVEL GENETIC ABNORMALITIES IN B-OTHER-ALL

B-other-ALL

Until recently, approximately 30% of BCP-ALL patients remained unclassified at the genetic level, having none of the established cytogenetic changes mentioned above. These patients were grouped together and classified as intermediate risk, within a so-called B-other-ALL subgroup (Fig. 1). In recent years, a number of distinct, recurrent abnormalities have emerged from within this highly genetically heterogeneous subgroup. Thus as B-other-ALL diminishes in size, these novel abnormalities have defined important new subgroups of variable outcome, as shown in Figures 3 and 4,6,26–36 replacing the default assignment of intermediate risk to these patients with increasingly more accurate prognostic information for improved treatments. These novel subgroups are described in more detail below.

Figure 3

Figure 3

Figure 4

Figure 4

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Ph-like/BCR-ABL1-like ALL

Two independent studies identified a subgroup of B-other patients from gene expression profiling with similar expression signatures to BCR-ABL1 positive patients, but lacking the BCR-ABL1 fusion.26,27,37,38 This group, named Ph-like/BCR-ABL1-like ALL, accounts for up to 15% of the original B-other-ALL subgroup and shows the same poor outcome as BCR-ABL1-positive ALL. The 2 studies used different methods and different cohorts to identify these patients, but, while the incidence of specific genetic abnormalities differed between the 2 cohorts, the association with poor risk was consistent.39 The Ph-like group, as defined by the COG, is characterized by a high incidence of IKZF1 deletions in approximately 70% of cases and over-expression of CRLF2 in about 50%. By contrast, in the BCR-ABL1-like group reported by Den Boer et al, the frequency of IKZF1 loss and CRLF2 over-expression was lower at 40% and 16%, respectively.40 Further investigations in Italian and Japanese cohorts have also identified patients with a similar gene expression profile to BCR-ABL1 positive patients, but again the spectra of genetic abnormalities in these cohorts were distinct.41,42 As a consensus gene expression profile to define this patient subgroup has failed to emerge, individual international study groups have chosen a range of different approaches to identify these cases. For example, COG has developed a TaqMan-based reverse transcriptase PCR low-density array based on the expression of 8 or 15 genes to identify Ph-like-ALL.31,43 Nevertheless, in both of the original studies, a similar proportion of patients harbored novel fusions involving kinase genes, in about 17% of cases.31,43–45 Thus, alternative screening approaches, for example, using FISH and RT-PCR, for the detection of the genetic abnormalities underlying these signatures, is proving to be clinically useful.46

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ABL-class fusions

Approximately 10% of patients in the Ph-like subgroup have fusions involving the tyrosine kinase genes: ABL1, ABL2, PDGFRB, PDGFRA, and CSF1R.31,43–45 Multiple and overlapping partner genes have been described for each kinase gene (Fig. 5).31,43–48 Many of these fusions have been reported in only single cases; however, a number has been shown to be recurrent. The most frequently identified fusion is EBF1-PDGFRB, which occurs in approximately 3% of the original B-other-ALL cohort.46 NUP214-ABL1 fusion, a common finding in T-ALL, has now also been identified among this subgroup.27,31,49 The MEF2D-CSF1R and ATF7IP-PDGFRB fusions, as a result of t(1;5)(q21;q33) and t(5;12)(p13;q33) translocations, respectively, have also been reported in a number of patients.50,51

Figure 5

Figure 5

As with the BCR-ABL1 fusion, the 5′ sequences of the partner gene are fused to the 3′ sequences of the kinase gene, resulting in constitutive kinase activity. Treatment with tyrosine kinase inhibitors (TKI), in addition to chemotherapy, has led to improvements in outcome for BCR-ABL1 positive ALL patients.52 Similarly, it has been shown that patients with ABL-class fusions respond well to treatment with TKI. For instance, case reports have described patients with EBF1-PDGRFB, who were refractory to conventional induction chemotherapy, showing complete response to imatinib.31,46,53,54 Experimental studies in vitro and in vivo have shown that cells from patients with other ABL-class fusions may also be responsive to TKI.27,31,50,51 As these patients are often refractory to induction therapies or have high levels of MRD,46 TKI treatment has become an important consideration when designing screening algorithms for childhood ALL.55

Rare fusions involving other kinase genes, including NTRK3, FGFR1, TYK2, and BLNK, have been reported in Ph-like ALL, for which specific inhibitors may be available for modified treatment in the future.31,43,45

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Aberrations in the JAK-STAT signaling pathway

Deregulation of the cytokine receptor gene, CRLF2, occurs in 5% of childhood BCP-ALL overall.56 There are 3 genetic mechanisms by which CRLF2-deregulation (CRLF2-d) can occur: (1) a cryptic translocation involving chromosome 14, (2) an interstitial deletion in the pseudo-autosomal region (PAR1) of the sex chromosomes at Xp22 and Yp11, and (3) rarely activating mutations, such as CRLF2-F232C. The former 2 mechanisms result in over-expression of CRLF2 as a result of the gene being placed under the transcriptional control of either the IGH enhancer at 14q32 (IGH-CRLF2) or the P2RY8 promoter in the PAR1 region (P2RY8-CRLF2).21 CRLF2 rearrangements, particularly as a result of P2RY8-CRLF2, have been shown to occur within all BCP-ALL cytogenetic subgroups; however, it is more prevalent in some groups than others. For example, it is present in approximately 50% of the B-other-ALL subgroup, Ph-like ALL31,57 and 20% of iAMP21-ALL.10 Notably, CRLF2-d occurs in around 60% of patients with Down syndrome ALL.58 The prognostic relevance of CRLF2-d is unclear. While some studies have reported poor EFS for CRLF2 rearranged patients, in other cohorts the outcome has been reported as intermediate.56,59,60 For example, CRLF2-d patients treated on the UK treatment trial, ALL97, had a similar outcome to those in the intermediate cytogenetic risk group (OS at 5 years 81% vs 85%). In around 40% of patients, the CRLF2 rearrangement is accompanied by activating mutations of JAK1 or JAK2, resulting in constitutive JAK-STAT signaling.60 It has been shown that CRLF2 rearranged cells are sensitive to JAK inhibitors, which raise the potential for targeted treatment of these patients.61,62 In fact a Phase 2 study of the JAK inhibitor, Ruxolitinib, with chemotherapy in childhood ALL is currently in progress (ClinicalTrials.gov Identifier: NCT02723994).

Rearrangements of JAK2 other than mutations, have been reported at a low incidence, in individual cases of ALL.30,63 However, approximately 7% of patients within the Ph-like subgroup harbor fusion genes that preserve the kinase domain of JAK2.31,64 A range of fusion partners has been reported (Fig. 5) of which the most common is PAX5. It fuses to JAK2 as the result of a cryptic inversion involving the short arm of chromosome 9. The SSBP2-JAK2 fusion arises from the translocation, t(5;9)(q14;p23). Primary patient cells harboring JAK2 fusions have shown sensitivity to Ruxolitinib in experimental studies,27,31,65 showing promise for targeted therapies in cases with JAK2 rearrangements, as well as mutations.

The EPOR gene at 19p13, which encodes the erythropoietin receptor, is also a recurrent molecular target in Ph-like ALL.27,31,66 The IGH-EPOR rearrangement has been identified from the reciprocal translocation, t(14;19)(q32;p13), readily visible by cytogenetics and FISH.67 However, a subsequent study revealed a number of cytogenetically cryptic rearrangements involving EPOR, including insertions of EPOR into the IGH or IGK loci, as well as intrachromosomal inversions that place EPOR upstream of the LAIR1 gene at 19q13.66 Unlike t(14;19)(q32;p13), these abnormalities cannot be detected by FISH and their identification relies on Next-Generation Sequencing technologies. However, the common consequence of all EPOR rearrangements is over-expression of a truncated EPOR protein, which is hypersensitive to erythropoietin and results in activated JAK-STAT signaling. As for other JAK-STAT-related abnormalities, EPOR-rearranged patient cells show sensitivity to JAK inhibitors.66

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DUX4-rearranged ALL

Several groups have recently described a distinct subgroup of B-other-ALL with rearrangements of the DUX4 gene.28,34,68 The existence of this group had long been recognized from gene expression studies, which noted a cluster of cytogenetically unclassified patients with a distinct gene expression profile.69 Genomic studies showed that more than 50% of patients within this cluster harbored intragenic deletions of ERG.38,70 ERG deletions occurred exclusively within this subgroup, although they were not considered to be primary genetic abnormalities, as they were often subclonal and inconsistent between diagnosis and relapse.29,71,72 Subsequent transcriptome studies revealed that all patients with this gene expression profile showed over-expression of DUX4, driven by insertion into the IGH locus in the majority of cases.28,34,68 Despite an incidence of 5% in childhood BCP-ALL, this abnormality remained elusive until recently, likely due to the small size of the rearrangement, the repetitive nature of the gene, up to 100 copies of DUX4 can be present within a normal genome, and its location within the subtelomeric regions of both chromosomes 4 and 10. These features also mean that DUX4 rearrangements are difficult to identify by FISH or standard techniques of PCR. Although attempts are being made to develop a simple diagnostic test to identify these patients, transcriptome sequencing remains the most reliable detection method for expression of DUX4 as well as the DUX4 rearrangement itself. Due to the specific association between ERG deletions and DUX4 rearrangements, an alternative diagnostic strategy would be to use ERG deletions as a surrogate marker for the identification of DUX4 rearranged patients. Several studies have shown that deletions of ERG are associated with a good outcome when treated on standard therapies, which is not attenuated by the presence of poor risk features, such as loss of IKZF1 and intermediate MRD levels.29,72

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ZNF384 fusions

The ZNF384 gene at 12p13 is the target of multiple recurrent translocations. Sporadic cases of ZNF384 fusions were first described in the early 2000s from investigations into rare but recurrent translocations identified by cytogenetics, including t(12;17)(p13;q11), t(12;22)(p13;q12), and t(12;19)(p13;p13).73–76 More recently genome and transcriptome sequencing has shown that up to 6% of children and 15% of adults with BCP-ALL harbor ZNF384 rearrangements.36,68,77–79 Their mutual exclusivity from other established chromosomal abnormalities has indicated that these rearrangements define a new subgroup, which has emerged from B-other-ALL. The fusion genes include almost all of the coding sequence of the ZNF384 gene translocated to a range of 5′ partner genes, including EP300 (22q13), CREBBP (16p13), TAF15 (17q12), SYNRG (17q12), EWSR1 (22q21), TCF3 (19p13), BMP2K (4q21), SMARCA2 (9q24), and ARID1B (6q25). Patients with ZNF384 fusions show similar gene expression profiles, distinct from other subtypes of BCP-ALL, and share a characteristic immunophenotype with low CD10 and aberrant expression of the myeloid markers CD13 and/or CD33.36 Further studies are required to determine the true prognostic significance of ZNF384 rearrangements, as currently there is debate over whether the partner gene has an effect on outcome. However, overall results from small cohorts indicate that they have an intermediate prognosis.36,78

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MEF2D fusions

Rearrangements involving the MEF2D gene, located to chromosome 1q22, have been reported in approximately 5% of B-other-ALL patients.35,80 The first report of a MEF2D fusion in ALL was MEF2D-DAZAP1, occurring as a result of the translocation, t(1;19)(q22;p13).73,81,82 More recently, novel fusion partner genes have been identified, of which BCL9 (1q21) is the most common. The close proximity of ZNF384 and BCL9 on chromosome 1 has made detection of this particular fusion difficult by cytogenetics or FISH. However, as MEF2D fusions are frequently associated with copy number abnormalities at both the MEF2D and partner gene loci, copy number arrays may provide clues to the presence of these fusions, in particular MEF2D-BCL9.35 Other fusion partners include CSF1R (5q33), SS18 (18q11), FOXJ2 (12p13), and HNRNPUL1 (19q13). The MEF2D-CSF1R fusion, mentioned above, is associated with a Ph-like gene expression signature and cells expressing this fusion have been shown to be sensitive to TKI treatment.35,51 The remaining MEF2D fusions share a distinct gene expression profile, resulting from deregulation of MEF2D targets. MEF2D rearrangements occur in older children and adolescents and have been associated with an inferior outcome.35,80 Leukemic cells expressing MEF2D fusion have been shown to be sensitive to treatment with histone deacetylation inhibitors, highlighting the potential for targeted therapies in these patients.35,80

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Abnormalities of PAX5

Cytogenetically visible abnormalities of the short arm of chromosome 9 are frequent in B-other-ALL. The majority are visible deletions of PAX5, which have also been observed across all BCP-ALL subtypes and are often associated with deletions of CDKN2A/B. 26,33,83 A number of recurrent chromosomal abnormalities, including translocations and dicentric chromosomes,84 have been reported, particularly in B-other-ALL, in which PAX5 is targeted.30,83 The consequence of many of these aberrations is whole or partial deletion of the PAX5 gene; however, a subset of them result in the expression of in-frame fusion genes encoding chimeric proteins.85 The PAX5 gene encodes a transcription factor, which plays a key role in B-cell commitment and maintenance.86

The most frequently reported abnormality is dic(9;20)(p13;q11), found in 1% to 2% of BCP-ALL overall, although it is usually restricted to the B-other-ALL subgroup, being mutually exclusive of the major cytogenetic abnormalities.87–89 Although rearrangements may appear to be identical by cytogenetics, the breakpoints within PAX5 and 20q11 are heterogeneous at the molecular level, suggesting that loss of genetic material rather than expression of a fusion protein is the functional consequence of this aberration.90,91 The dicentric chromosome, dic(9;12)(p11∼12;p11∼13), occurs at a lower frequency than dic(9;20). It is often found within ETV6-RUNX1 positive ALL, where it is associated with loss of the nontranslocated copy of ETV6 and the entire PAX5 gene.6,92 By contrast, when it occurs in B-other-ALL, it is present as a PAX5-ETV6 fusion.92,93 Expression of this PAX5-ETV6 fusion in B-cell precursor cells has been shown to alter gene expression, with an opposite dominant effect over wild-type PAX5, which is thought to be the driver of leukemogenesis in these patients.94 PAX5 has been described as a promiscuous gene, as many other fusion gene partners have been identified, although often only reported in few or single cases.30,83 Therefore, elucidation of the functional consequences and prognostic significance of PAX5 fusions remains unclear.

Intragenic amplification of PAX5 exons 2 to 5 (PAX5 AMP) has been described in a small but distinctive subgroup of around 3% of B-other-ALL. The majority of patients with PAX5 AMP lack the recurrent cytogenetic alterations used in risk stratification for treatment, suggesting that it defines a novel subgroup of BCP-ALL, which is relapse prone (occurring in approximately 40% of cases) and associated with a poor outcome (5-year EFS and OS rates of 49% and 67%, respectively).95

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ETV6-RUNX1-like-ALL

Recently, a subgroup of patients with ALL have been identified, who share the same gene expression profile and/or methylation signature as ETV6-RUNX1 positive patients, but lack the ETV6-RUNX1 fusion.8,34 Within this group, novel gene fusions and deletions of the ETV6, RUNX1, and IKZF1 genes have been described. It is tempting to speculate that ETV6-RUNX1-like patients may also share the same good prognosis as ETV6-RUNX1-positive patients and indeed few relapses have been reported among them. However, the number of patients identified to date is small, highlighting the need for further trial-based studies.34,96

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IGH rearrangements

Rearrangements involving the IGH locus are seen in approximately 5% of ALL overall, occurring in both the T- and B-lineage,32 although individually they are rare. They essentially form part of the B-other-ALL group, as translocations have been noted with a range of partner genes (Fig. 3), including CRLF2, EPOR, and DUX4, as discussed above. Other partners have been reported, which include IL3 at 5q31, a rare translocation with a strong association with hypereosinophilia as reported by WHO,9 ID4 at 6p1497 and 5 members of the CEBP gene family: CEBPA (19q13), CEBPB (20q13), CEBPD (8q11), CEBPE (14q11), and CEBPG (19q13).98 Whether IGH can define these abnormalities as belonging to an independent group is somewhat unlikely, regarding the range of functional roles of the partner genes. The important molecular consequence of all IGH translocations is high levels of over-expression of the partner gene as a result of its juxtaposition to the potent IGH enhancer. IGH rearrangements are present in all age groups, with the peak incidence in adolescents and young adults. Collectively, they have been associated with an adverse outcome in adults, although they did not represent an independent prognostic factor in children and adolescents.32

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CONCLUSIONS AND FUTURE PERSPECTIVES

Chromosomal abnormalities have provided a reliable basis on which risk stratification of ALL has been built over the last 4 decades. As a result of continuous advances in new state-of-the-art technologies of Next-Generation Sequencing of genomes and transcriptomes, as well as improved resolution for detection of copy number changes, the identification of novel genetic abnormalities in ALL over recent years has significantly refined risk stratification algorithms. As a result, the proportion of B-other-ALL cases in which a genetic abnormality has not been identified has diminished significantly (Fig. 3). With further technological advances, it is likely that every case of ALL will become assigned to a genetic subtype of known clinical relevance. The wide choice of targeted molecular methodologies now available for the detection of the full range of genetic abnormalities means that individual laboratories can select the screening approaches most suited to their expertise and traditions, in order to achieve the same results. Targeted approaches are highly adaptable, allowing the integration of novel targets for each new abnormality as it is discovered. As many of the recently described abnormalities are rare, continued investigations at the biological and clinical levels are essential to determine their true prognostic relevance.

The explosion of technologies has not only accurately defined the genetic subtype of the majority of ALL patients, but has been instrumental in highlighting novel molecular targets for therapy. Following the paradigm changing discovery of the sensitivity of BCR-ABL1- positive leukemias to treatment with TKI, a range of specific genetic subtypes has been identified, which not only show response to TKI treatments experimentally, but also in patients with otherwise refractory disease, as exemplified by carriers of the ABL-class fusions, notably EBF1-PDGFRB. This specific modification of treatment for patients responsive to TKI has been a major breakthrough, which hopefully will be mirrored by targeted treatment of a wider range of abnormalities in the near future, to assist in reduction of toxicity associated with current conventional therapies.

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References

1. Stiller CA, Kroll ME, Boyle PJ, et al. Population mixing, socioeconomic status and incidence of childhood acute lymphoblastic leukaemia in England and Wales: analysis by census ward. Br J Cancer 2008; 98:1006–1011.
2. Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet 2013; 381:1943–1955.
3. Hunger SP, Mullighan CG. Acute lymphoblastic leukemia in children. N Engl J Med 2015; 373:1541–1552.
4. Diller L, Chow EJ, Gurney JG, et al. Chronic disease in the Childhood Cancer Survivor Study cohort: a review of published findings. J Clin Oncol 2009; 27:2339–2355.
5. Harrison CJ, Johansson B. Heim S, Mitelman F. Acute lymphoblastic leukaemia. Cancer Cytogenetics John Wiley and Son Inc, 3rd edHoboken, NJ:2009.
6. Moorman AV, Ensor HM, Richards SM, et al. Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial. Lancet Oncol 2010; 11:429–438.
7. Andersson AK, Ma J, Wang J, et al. The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias. Nat Genet 2015; 47:330–337.
8. Nordlund J, Backlin CL, Zachariadis V, et al. DNA methylation-based subtype prediction for pediatric acute lymphoblastic leukemia. Clin Epigenetics 2015; 7:11.
9. Wang S, He G. 2016 Revision to the WHO classification of acute lymphoblastic leukemia. J Transl Int Med 2016; 4:147–149.
10. Harrison CJ, Moorman AV, Schwab C, et al. An international study of intrachromosomal amplification of chromosome 21 (iAMP21): cytogenetic characterization and outcome. Leukemia 2014; 28:1015–1021.
11. Harewood L, Robinson H, Harris R, et al. Amplification of AML1 on a duplicated chromosome 21 in acute lymphoblastic leukemia: a study of 20 cases. Leukemia 2003; 17:547–553.
12. Rand V, Parker H, Russell LJ, et al. Genomic characterization implicates iAMP21 as a likely primary genetic event in childhood B-cell precursor acute lymphoblastic leukemia. Blood 2011; 117:6848–6855.
13. Li Y, Schwab C, Ryan SL, et al. Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia. Nature 2014; 508:98–102.
14. Harrison CJ. Blood spotlight on iAMP21 acute lymphoblastic leukemia (ALL), a high-risk pediatric disease. Blood 2015; 125:1383–1386.
15. Benard-Slagter A, Zondervan I, de Groot K, et al. Digital multiplex ligation-dependent probe amplification for detection of key copy number alterations in T- and B-cell lymphoblastic leukemia. J Mol Diagn 2017; 19:659–672.
16. Robinson HM, Broadfield ZJ, Cheung KL, et al. Amplification of AML1 in acute lymphoblastic leukemia is associated with a poor outcome. Leukemia 2003; 17:2249–2250.
17. Moorman AV, Richards SM, Robinson HM, et al. Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21). Blood 2007; 109:2327–2330.
18. Moorman AV, Robinson H, Schwab C, et al. Risk-directed treatment intensification significantly reduces the risk of relapse among children and adolescents with acute lymphoblastic leukemia and intrachromosomal amplification of chromosome 21: a comparison of the MRC ALL97/99 and UKALL2003 trials. J Clin Oncol 2013; 31:3389–3396.
19. Heerema NA, Carroll AJ, Devidas M, et al. Intrachromosomal amplification of chromosome 21 is associated with inferior outcomes in children with acute lymphoblastic leukemia treated in contemporary standard-risk children's oncology group studies: a report from the children's oncology group. J Clin Oncol 2013; 31:3397–3402.
20. Ryan SL, Matheson E, Grossmann V, et al. The role of the RAS pathway in iAMP21-ALL. Leukemia 2016; 30:1824–1831.
21. Russell LJ, Capasso M, Vater I, et al. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia. Blood 2009; 114:2688–2698.
22. Mullighan CG, Collins-Underwood JR, Phillips LA, et al. Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia. Nat Genet 2009; 41:1243–1246.
23. Ivanov Ofverholm I, Tran AN, Olsson L, et al. Detailed gene dose analysis reveals recurrent focal gene deletions in pediatric B-cell precursor acute lymphoblastic leukemia. Leuk Lymphoma 2016; 57:2161–2170.
24. Perez-Garcia A, Ambesi-Impiombato A, Hadler M, et al. Genetic loss of SH2B3 in acute lymphoblastic leukemia. Blood 2013; 122:2425–2432.
25. Yano M, Imamura T, Asai D, et al. Clinical significance of SH2B3 (LNK) expression in paediatric B-cell precursor acute lymphoblastic leukaemia. Br J Haematol 2017; in press.
26. Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol 2009; 10:125–134.
27. Roberts KG, Morin RD, Zhang J, et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell 2012; 22:153–166.
28. Zhang J, McCastlain K, Yoshihara H, et al. Deregulation of DUX4 and ERG in acute lymphoblastic leukemia. Nat Genet 2016; 48:1481–1489.
29. Clappier E, Auclerc MF, Rapion J, et al. An intragenic ERG deletion is a marker of an oncogenic subtype of B-cell precursor acute lymphoblastic leukemia with a favorable outcome despite frequent IKZF1 deletions. Leukemia 2014; 28:70–77.
30. Nebral K, Denk D, Attarbaschi A, et al. Incidence and diversity of PAX5 fusion genes in childhood acute lymphoblastic leukemia. Leukemia 2009; 23:134–143.
31. Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med 2014; 371:1005–1015.
32. Russell LJ, Enshaei A, Jones L, et al. IGH@ translocations are prevalent in teenagers and young adults with acute lymphoblastic leukemia and are associated with a poor outcome. J Clin Oncol 2014; 32:1453–1462.
33. Schwab CJ, Chilton L, Morrison H, et al. Genes commonly deleted in childhood B-cell precursor acute lymphoblastic leukemia: association with cytogenetics and clinical features. Haematologica 2013; 98:1081–1088.
34. Lilljebjorn H, Henningsson R, Hyrenius-Wittsten A, et al. Identification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia. Nat Commun 2016; 7:11790.
35. Gu Z, Churchman M, Roberts K, et al. Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia. Nat Commun 2016; 7:13331.
36. Hirabayashi S, Ohki K, Nakabayashi K, et al. ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype. Haematologica 2017; 102:118–129.
37. Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 2009; 360:470–480.
38. Harvey RC, Mullighan CG, Wang X, et al. Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome. Blood 2010; 116:4874–4884.
39. Boer JM, Marchante JR, Horstmann MA, et al. BCR-ABL1-like cases in pediatric acute lymphoblastic leukemia: a comparison between COG/St. Jude and Dutch DCOG signatures. Haematologica 2015; 100:e354–e357.
40. van der Veer A, Waanders E, Pieters R, et al. Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL. Blood 2013; 122:2622–2629.
41. Kiyokawa N, Iijima K, Yoshihara H, et al. An analysis of Ph-like ALL in Japanese patients. Blood 2013; 122:352.
42. Te Kronnie G, Silvestri D, Vendramini E, et al. Philadelphia-like signature in childhood acute lymphoblastic leukemia: the AIEOP experience. Blood 2013; 122:353.
43. Reshmi SC, Harvey RC, Roberts KG, et al. Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's Oncology Group. Blood 2017; 129:3352–3361.
44. Boer JM, Steeghs EM, Marchante JR, et al. Tyrosine kinase fusion genes in pediatric BCR-ABL1-like acute lymphoblastic leukemia. Oncotarget 2017; 8:4618–4628.
45. Roberts KG, Pei D, Campana D, et al. Outcomes of children with BCR-ABL1-like acute lymphoblastic leukemia treated with risk-directed therapy based on the levels of minimal residual disease. J Clin Oncol 2014; 32:3012–3020.
46. Schwab C, Ryan SL, Chilton L, et al. EBF1-PDGFRB fusion in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL): genetic profile and clinical implications. Blood 2016; 127:2214–2218.
47. Roberts KG. The biology of Philadelphia chromosome-like ALL. Best Pract Res Clin Haematol 2017; 30:212–221.
48. Imamura T, Kiyokawa N, Kato M, et al. Characterization of pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia with kinase fusions in Japan. Blood Cancer J 2016; 6:e419.
49. Eyre T, Schwab CJ, Kinstrie R, et al. Episomal amplification of NUP214-ABL1 fusion gene in B-cell acute lymphoblastic leukemia. Blood 2012; 120:4441–4443.
50. Kobayashi K, Mitsui K, Ichikawa H, et al. ATF7IP as a novel PDGFRB fusion partner in acute lymphoblastic leukaemia in children. Br J Haematol 2014; 165:836–841.
51. Lilljebjorn H, Agerstam H, Orsmark-Pietras C, et al. RNA-seq identifies clinically relevant fusion genes in leukemia including a novel MEF2D/CSF1R fusion responsive to imatinib. Leukemia 2014; 28:977–979.
52. Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol 2009; 27:5175–5181.
53. Lengline E, Beldjord K, Dombret H, et al. Successful tyrosine kinase inhibitor therapy in a refractory B-cell precursor acute lymphoblastic leukemia with EBF1-PDGFRB fusion. Haematologica 2013; 98:e146–e148.
54. Weston BW, Hayden MA, Roberts KG, et al. Tyrosine kinase inhibitor therapy induces remission in a patient with refractory EBF1-PDGFRB-positive acute lymphoblastic leukemia. J Clin Oncol 2013; 31:e413–e416.
55. O’Connor D, Moorman AV, Wade R, et al. Use of minimal residual disease assessment to redefine induction failure in pediatric acute lymphoblastic leukemia. J Clin Oncol 2017; 35:660–667.
56. Ensor HM, Schwab C, Russell LJ, et al. Demographic, clinical and outcome features of children with acute lymphoblastic leukemia and CRLF2 deregulation: results from the MRC ALL97 clinical trial. Blood 2011; 117:2129–2136.
57. Buitenkamp TD, Pieters R, Gallimore NE, et al. Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations. Leukemia 2012; 26:2204–2211.
58. Hertzberg L, Vendramini E, Ganmore I, et al. Down syndrome acute lymphoblastic leukemia: a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the iBFM Study Group. Blood 2010; 115:1006–1017.
59. Cario G, Zimmermann M, Romey R, et al. Presence of the P2RY8-CRLF2 rearrangement is associated with a poor prognosis in non-high-risk precursor B-cell acute lymphoblastic leukemia in children treated according to the ALL-BFM 2000 protocol. Blood 2010; 115:5393–5397.
60. Harvey RC, Mullighan CG, Chen IM, et al. Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. Blood 2010; 115:5312–5321.
61. Maude SL, Tasian SK, Vincent T, et al. Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood 2012; 120:3510–3518.
62. Tasian SK, Doral MY, Borowitz MJ, et al. Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia. Blood 2012; 120:833–842.
63. Poitras JL, Dal Cin P, Aster JC, et al. Novel SSBP2-JAK2 fusion gene resulting from a t (5;9)(q14.1;p24.1) in pre-B acute lymphocytic leukemia. Genes Chromosomes Cancer 2008; 47:884–889.
64. Steeghs EMP, Jerchel IS, de Goffau-Nobel W, et al. JAK2 aberrations in childhood B-cell precursor acute lymphoblastic leukemia. Oncotarget 2017; 8:89923–89938.
65. Schinnerl D, Fortschegger K, Kauer M, et al. The role of the Janus-faced transcription factor PAX5-JAK2 in acute lymphoblastic leukemia. Blood 2015; 125:1282–1291.
66. Iacobucci I, Li Y, Roberts KG, et al. Truncating erythropoietin receptor rearrangements in acute lymphoblastic leukemia. Cancer Cell 2016; 29:186–200.
67. Russell LJ, De Castro DG, Griffiths M, et al. A novel translocation, t (14;19)(q32;p13), involving IGH@ and the cytokine receptor for erythropoietin. Leukemia 2009; 23:614–617.
68. Yasuda T, Tsuzuki S, Kawazu M, et al. Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults. Nat Genet 2016; 48:569–574.
69. Yeoh EJ, Ross ME, Shurtleff SA, et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 2002; 1:133–143.
70. Mullighan CG, Miller CB, Su X, et al. ERG deletions define a novel subtype of B-progenitor acute lymphoblastic leukemia. Blood 2007; 110:691.
71. Potuckova E, Zuna J, Hovorkova L, et al. Intragenic ERG deletions do not explain the biology of ERG-related acute lymphoblastic leukemia. PLoS ONE 2016; 11:e0160385.
72. Zaliova M, Zimmermannova O, Dorge P, et al. ERG deletion is associated with CD2 and attenuates the negative impact of IKZF1 deletion in childhood acute lymphoblastic leukemia. Leukemia 2014; 28:182–185.
73. Barber KE, Harrison CJ, Broadfield ZJ, et al. Molecular cytogenetic characterization of TCF3 (E2A)/19p13.3 rearrangements in B-cell precursor acute lymphoblastic leukemia. Genes Chromosomes Cancer 2007; 46:478–486.
74. La Starza R, Aventin A, Crescenzi B, et al. CIZ gene rearrangements in acute leukemia: report of a diagnostic FISH assay and clinical features of nine patients. Leukemia 2005; 19:1696–1699.
75. Martini A, La Starza R, Janssen H, et al. Recurrent rearrangement of the Ewing's sarcoma gene, EWSR1, or its homologue, TAF15, with the transcription factor CIZ/NMP4 in acute leukemia. Cancer Res 2002; 62:5408–5412.
76. Zhong CH, Prima V, Liang X, et al. E2A-ZNF384 and NOL1-E2A fusion created by a cryptic t (12;19)(p13.3; p13.3) in acute leukemia. Leukemia 2008; 22:723–729.
77. Shago M, Abla O, Hitzler J, et al. Frequency and outcome of pediatric acute lymphoblastic leukemia with ZNF384 gene rearrangements including a novel translocation resulting in an ARID1B/ZNF384 gene fusion. Pediatr Blood Cancer 2016; 63:1915–1921.
78. Liu YF, Wang BY, Zhang WN, et al. Genomic profiling of adult and pediatric B-cell acute lymphoblastic leukemia. EBioMedicine 2016; 8:173–183.
79. Qian M, Zhang H, Kham SK, et al. Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP. Genome Res 2017; 27:185–195.
80. Suzuki K, Okuno Y, Kawashima N, et al. MEF2D-BCL9 fusion gene is associated with high-risk acute B-cell precursor lymphoblastic leukemia in adolescents. J Clin Oncol 2016; 34:3451–3459.
81. Prima V, Gore L, Caires A, et al. Cloning and functional characterization of MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins created by a variant t (1;19)(q23;p13.3) in acute lymphoblastic leukemia. Leukemia 2005; 19:806–813.
82. Yuki Y, Imoto I, Imaizumi M, et al. Identification of a novel fusion gene in a pre-B acute lymphoblastic leukemia with t (1;19)(q23;p13). Cancer Sci 2004; 95:503–507.
83. Mullighan CG, Goorha S, Radtke I, et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 2007; 446:758–764.
84. Heerema NA, Sather HN, Sensel MG, et al. Association of chromosome arm 9p abnormalities with adverse risk in childhood acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood 1999; 94:1537–1544.
85. Fortschegger K, Anderl S, Denk D, et al. Functional heterogeneity of PAX5 chimeras reveals insight for leukemia development. Mol Cancer Res 2014; 12:595–606.
86. Medvedovic J, Ebert A, Tagoh H, et al. Pax5: a master regulator of B cell development and leukemogenesis. Adv Immunol 2011; 111:179–206.
87. Forestier E, Gauffin F, Andersen MK, et al. Clinical and cytogenetic features of pediatric dic (9;20)(p13.2;q11.2)-positive B-cell precursor acute lymphoblastic leukemias: a Nordic series of 24 cases and review of the literature. Genes Chromosomes Cancer 2008; 47:149–158.
88. Heerema NA, Maben KD, Bernstein J, et al. Dicentric (9;20)(p11;q11) identified by fluorescence in situ hybridization in four pediatric acute lymphoblastic leukemia patients. Cancer Genet Cytogenet 1996; 92:111–115.
89. Clark R, Byatt SA, Bennett CF, et al. Monosomy 20 as a pointer to dicentric (9;20) in acute lymphoblastic leukemia. Leukemia 2000; 14:241–246.
90. An Q, Wright SL, Moorman AV, et al. Heterogeneous breakpoints in patients with acute lymphoblastic leukemia and the dic (9;20)(p11-13;q11) show recurrent involvement of genes at 20q11.21. Haematologica 2009; 94:1164–1169.
91. Schoumans J, Johansson B, Corcoran M, et al. Characterisation of dic (9;20)(p11-13;q11) in childhood B-cell precursor acute lymphoblastic leukaemia by tiling resolution array-based comparative genomic hybridisation reveals clustered breakpoints at 9p13.2 and 20q11.2. Br J Haematol 2006; 135:492–499.
92. Gastier-Foster JM, Carroll AJ, Ell D, et al. Two distinct subsets of dic (9;12)(p12;p11.2) among children with B-cell precursor acute lymphoblastic leukemia (ALL): PAX5-ETV6 and ETV6-RUNX1 rearrangements: a report from the Children's Oncology Group. Blood 2007; 110:1439.
93. Strehl S, Konig M, Dworzak MN, et al. PAX5/ETV6 fusion defines cytogenetic entity dic (9;12)(p13;p13). Leukemia 2003; 17:1121–1123.
94. Fazio G, Cazzaniga V, Palmi C, et al. PAX5/ETV6 alters the gene expression profile of precursor B cells with opposite dominant effect on endogenous PAX5. Leukemia 2013; 27:992–995.
95. Schwab C, Nebral K, Chilton L, et al. Intragenic amplification of PAX5: a novel subgroup in B-cell precursor acute lymphoblastic leukemia? Blood Adv 2017; 1:1473–1477.
96. Zaliova M, Kotrova M, Bresolin S, et al. ETV6/RUNX1-like acute lymphoblastic leukemia: a novel B-cell precursor leukemia subtype associated with the CD27/CD44 immunophenotype. Genes Chromosomes Cancer 2017; 56:608–616.
97. Russell LJ, Akasaka T, Majid A, et al. t (6;14)(p22;q32): a new recurrent IGH@ translocation involving ID4 in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blood 2008; 111:387–391.
98. Akasaka T, Balasas T, Russell LJ, et al. Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blood 2007; 109:3451–3461.
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