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Current Opinion in Hematology:
doi: 10.1097/MOH.0000000000000050

Beyond Philadelphia: ‘Ph-like’ B cell precursor acute lymphoblastic leukemias – diagnostic challenges and therapeutic promises

Izraeli, Shaia,b,c

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Author Information

aChildhood Leukemia Research Center, Department of Pediatric Hematology Onclology, Edmond and Lily Safra Children Hospital

bSheba Medical Center, Tel Hashomer, Ramat Gan

cDepartment of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Correspondence to Shai Izraeli, MD, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel. Tel: +97235305943; e-mail:

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Purpose of review

The presence of the Philadelphia chromosome causing the fusion between BCR to ABL1 in B cell precursor acute lymphoblastic leukemias (ALLs) was associated with a particularly bad prognosis, which has been markedly improved with the addition of imatinib to chemotherapy. Recent genomic studies have lead to the identification of ‘Philadelphia like’ or ‘BCR-ABL1 like’ ALLs lacking BCR-ABL1 fusion.

Recent findings

About 10% of childhood ALL and a higher percentage of adolescents and adults with ALLs are characterized by activation of cytokine receptors and signaling kinases. Aberrant expression, point mutations or fusion translocations cause activation of either the ABL1 or JAK signaling pathways. In general, these leukemias are associated with worse prognosis. Preclinical studies and limited clinical experience suggest that these leukemias respond to tyrosine kinase inhibitors. Thus, their identification is important. However, as most of these fusion translocations are rare, their diagnosis is challenging.


The diagnosis of ‘Philadelphia like’ poor prognosis ALLs is technically challenging but of paramount importance as they are likely to respond to targeted therapy with currently available ABL or JAK inhibitors.

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It is appropriate to begin this review, with a tribute to the late Dr Janet Rowley. She discovered that the Philadelphia chromosome, described earlier by Knowels and Hungerford in chronic myeloid leukemia (CML), is created by a chromosomal translocation fusing chromosomes 9 and 22 (reviewed in [1▪]). This landmark discovery paved the way for the cloning of BCR-ABL1 and the development of tyrosine kinase inhibitors (TKIs) that dramatically changed the outcome of CML.

In addition to its role in CML, BCR-ABL1 is also the driving genetic event of 3–20% of B cell precursor-acute lymphoblastic leukemias (BCP-ALLs) in children and adults, respectively. BCR-ABL1 ALL has been associated with worse prognosis, and it has been a clear indication for hematopoietic stem cell transplantation in first remission for children and adults alike. Unlike CML, TKIs as single drugs are insufficient therapy for ALL, probably because of collaborating leukemogenic events that will be discussed below. Yet, the combination of TKIs with intensive chemotherapy improved dramatically the outcome of BCR-ABL1 positive ALL, increasing the cure rate of children to 70% or more and close to 50% of adults with BCR-ABL ALL [2▪,3▪▪,4▪,5]. This improvement is so remarkable that stem cell transplantation is not automatically indicated for all children with BCR-ABL1 ALL, although it remains so for adults with ALL [2▪,3▪▪,4▪,6▪,7▪]. It is likely that the incorporation of newer more potent TKIs [8–11] will enable further reduction of cytotoxic chemotherapy for this disease.  

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This perspective is focused on recent discoveries of subtypes of poor prognosis BCP-ALLs that similarly to BCR-ABL1 ALL are characterized by constitutive activation of kinases. The diagnosis of these leukemias is challenging, as many different and rare genetic aberrations have been described. Yet, diagnosis is imperative because of the therapeutic potential of available TKIs.

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The term ‘BCR-ABL1 like’ was coined by Den Boer who observed a subgroup of BCP-ALLs with similar gene expression profile to BCR-ABL1 ALLs [12▪▪]. I will use from here on the alternative name ‘Ph-like’ [13▪▪]. These leukemias lack the typical genetic aberrations characterizing BCP-ALLs – ETV6-RUNX1, E2A-PBX1, ERG or MLL rearrangements – and are usually not high-hyperdiploid. They are often associated with high-risk clinical features, such as a male sex, higher age and increased blast count at diagnosis. The presence of this gene expression signature is independently associated with a poor prognosis similar to the prognosis of BCR-ABL1 leukemias prior to the imatinib era. In the absence of clear diagnostic criteria, their exact prevalence is unknown, but it increases with age from about 10% in children to a high estimate of 30% of young adults with BCP-ALL [12▪▪,13▪▪,14].

Comprehensive genomic studies have revealed that Ph-like ALLs are characterized by activation of either the JAK or ABL-associated signaling pathways [13▪▪,15▪▪] (Fig. 1). The distinction between the two is important, as available TKIs are specific to either ABL or JAK pathways. The most common mechanism of activation is through genomic rearrangements that either cause overexpression of receptors through fusion with a strong promoter or enhancer or create chimeric proteins with a constitutive activation of a cytokine receptor or a kinase similarly to the BCR-ABL1 (Table 1). Many of these newly discovered aberrations have been shown experimentally to transform preleukemic cells. The kinase-driven proliferation and prosurvival signals are accompanied by additional genetic aberrations in lymphoid transcription factors blocking differentiation.

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Table 1
Table 1
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About half of Ph-like BCP-ALLs are characterized by aberrant expression of CRLF2. Normally, CRLF2 together with interleukin-7 receptor α (IL7R) form the receptor to thymic stromal lymphopietin. The abnormal expression of CRLF2 is caused by either translocation into the immunoglobulin heavy (IgH) locus or by fusion with the upstream promoter of a constitutive expressed gene P2RY8. This expression is often associated with additional mutations that activate cytokine independent signaling. These are either activating mutations in CRLF2 or its associated receptor IL7R or in the downstream Janus kinase 2 (JAK2) or JAK1 enzymes. Interestingly, mutations in JAK2 or JAK1 are identified almost always only in the context of CRLF2 aberrant expression [14]. This may be related to the unique lymphoid type of mutations in JAK2 that most commonly replace or displace Arginine 683 unlike the V617F mutation found only in myeloproliferative neoplasms. Both mutations constitutively activate JAK2, and the reason for the intriguing lineage specificity is presently unknown (reviewed in [16▪]). Preclinical studies demonstrated that the activation of this pathway is transforming in vitro and in vivo[17▪]. Initially discovered in 60% of BCP-ALL in children with Down syndrome [18▪], CRLF2-IL7R-JAK-STAT activation was later identified in about 5% of sporadic ALLs and has been generally associated with worse prognosis although the prognostic significance depends on the specific treatment protocol. As most of these discoveries were reported earlier than 2012, the reader is directed to a recent comprehensive review [16▪].

Activation of JAK signaling is achieved also through less common genetic events. The receptor to IL7 is rarely activated by mutations that either insert cystein to the extracellular domain [19] or change the three-dimensional structure of the transmembrane domain (Shochat et al., Blood, in press). Aberrant expression of the receptor to Erythropoietin by its translocation into the IgH enhancer locus activates JAK2 in a similar fashion to CRLF2 [13▪▪,15▪▪,20,21]. RNAseq has revealed fusions of JAK2 in about 20% of Ph-like ALL with a variety of partners, such as BCR-JAK2, STRN3-JAK2 and PAX5-JAK2 [13▪▪,15▪▪]. In all of the fusions, the kinase domain of JAK2 is retained and is constitutively activated. The fusion with PAX5 is recurrent [22] and conveys ‘two hits’ in one rearrangement – loss of one allele of the differentiation factor PAX5 coupled with activation of JAK2. This presumably results in block of differentiation and increased proliferation of B lymphoid precursors.

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Unlike the heterogeneity in the types of genomic aberrations in the ‘JAK pathway’ ALLs, the ABL activating lesions are all fusion genes. Most are multiple different ABL1 and ABL2 fusions that are structurally similar to BCR-ABL1 and cause constitutive activation of ABL kinase [13▪▪,15▪▪,23]. One of these fusions NUP214-ABL1 has also been associated with T acute lymphoblastic leukemia [24]. In addition, two fusions causing constitutive activation of cytokine receptors have been identified. Platelet-derived growth factor receptor beta (PDGFRB) is a tyrosine kinase receptor that is involved in TKIs sensitive myeloid neoplasms [25,26▪]. A recurrent fusion early B cell factor (EBF1)-PDGFRB is present in approximately 8% of Ph-like ALL (hence 1% or less of childhood BCP-ALL). Similarly to the PAX5-JAK2 fusion, this translocation causes loss of a B cell differentiation factor, EBF, and a constitutive activation of a tyrosine kinase, PDGFRB.

Colony stimulating factor 1 receptor (CSF1R) is another myeloid receptor involved in a recurrent fusion translocation in Ph-like ALL. Activation of CSF1R is known in myelomonocytic leukemias [27,28▪]. Li et al.[15▪▪] reported a recurrent SSBP2-CSF1R in Ph-like ALL enrolled on the COG AALL0232 high-risk B-ALL trial. Interestingly, SSBP2, a single strand DNA binding protein involved in the regulation of genomic stability, is cophosphorylated with ABL1 upon cytokine receptor signaling [29] and was reported to be fused to JAK2 in a case of BCP-ALL [30] and to be involved in T acute lymphoblastic leukemia [31].

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The hallmarks of acute leukemia are clonal enhancement of self-renewal, proliferation and survival and arrested differentiation of hematopoietic progenitors. Speck and Gilliland [32] proposed a conceptual model in which acute myeloid leukemia is caused by a combination of class I mutations enhancing proliferation and survival and class II mutations blocking differentiation. This model is relevant to BCP-ALL in which haploinsufficiency of B cell differentiation factors, such as PAX5, EBF1 or IKZF1, is common [33]. BCR-ABL1 and Ph-like leukemias are highly associated with deletion of IKZF1 encoding the transcription factor Ikaros. Deletion of a complete allele of IKZF1 or intragenic deletion of exons coding the DNA binding domain of Ikaros confer worse prognosis in general for ALL [34▪–36▪], although not for ERG-deleted ALL [37▪,38▪]. The worse prognosis is also relevant for BCR-ABL1 and Ph-like leukemias and persists even in patients treated with imatinib [36▪,39▪▪,40▪,41▪]. The synergy between BCR-ABL1 and haploinsufficiency of Ikaros has been formally demonstrated in mice [42].

Three recent studies suggest how inhibition of Ikaros predisposes to the development of BCP-ALL, especially kinase-driven ALL. They demonstrate that Ikaros depletion arrests B cell in the pre-B state and enhances kinase-dependent cell proliferation and self-renewal. Heizmann et al.[43▪▪] reported that Ikaros antagonizes IL7 signaling. Therefore, Ikaros deletion results in enhanced sensitivity to IL7 and activation of the JAK-STAT pathway. These observations may explain the association between CRLF2-IL7R-JAK-STAT activation and IKZF1 deletion.

The studies from the laboratories of Georgopoulos [44▪▪] and Busslinger, respectively [45] suggest that during the development of B cells in the bone marrow, there is an important transition between stroma-dependent proliferation and self-renewal and a stroma-independent stage in which pre-B cells complete their differentiation and leave the bone marrow to the blood and lymphoid organs. Ikaros mediates this transition. Pre-B cells expressing the ALL-associated dominant negative isoforms of Ikaros remain dependent on stroma on which they exhibit enhanced proliferation and self-renewal associated with ERK and PI3-kinase signaling and blocked differentiation. These cells eventually transform in vivo into BCP-ALL. Thus, the depletion of Ikaros primes pre-B cells to kinase signaling, possibly explaining the association of IKZF1 deletion with Ph and Ph-like ALL. The stroma dependency and preleukemic growth of pre-B cells lacking functional Ikaros is accompanied by upregulation of many integrins and activation of their downstream signaling kinases, such as focal adhesion kinase (FAK). BCR-ABL1 was previously reported to phosphorylate FAK [46], raising the intriguing hypothesis of synergistic activation of FAK by ABL activation and loss of Ikaros (Fig. 1). Georgopoulos et al.[44▪▪] further show that treatment with an oral bioavailable inhibitor of FAK and the closely related kinase Ptk2b (PF-562271) reversed the abnormal stroma adherence phenotype and caused apoptosis of the abnormal large pre-B cells carrying the mutated Ikaros protein in vitro and in vivo. Hence, for the first time, there is a potential therapeutic approach to antagonize the pro-leukemic effects of Ikaros deletions.

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In line with the leukemogenic effect of germline deletion of IKZF1 in mice, germline alterations in IKZF1 also predispose humans to BCP-ALL, as revealed by gene wide association studies [47–49]. Germline loss-of-function of PAX5, another B cell differentiation factor, has recently been associated with familial BCP-ALLs [50▪,51▪].

Two gene wide association studies have identified strong association of Ph-like BCP-ALL (or at least ‘B others’ ALLs) and inherited variant in GATA3 leading to its increased expression [52▪,53▪]. Why increased expression of GATA3 is linked to Ph-ALL is unclear. As GATA3 is a T cell differentiation factor, it is tempting to speculate that higher expression in a lymphoid progenitor functions as a B differentiation arresting stimulus, similarly to Ikaros or PAX5 deletions. It is important to stress that there may be confounding variables. For example, both Ph-like ALLs and the GATA3 variants are more common in children of Hispanic origin [54▪].

A rare familial leukemia syndrome directly linking the JAK-STAT pathway and BCP-ALL is caused by germline mutations in SH2B3 encoding the protein adaptor LNK. LNK suppresses JAK2. Hence, germline or somatic loss-of-function mutations in SH2B3 activates the JAK-STAT pathway and predisposes to Ph-like ALL. A recent study investigating BCP-ALL in mice lacking SH2B3 suggests that LNK is also a negative regulator of interleukin-11 which may be, therefore, another cytokine important in Ph-like BCP-ALL [55▪].

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This review focuses on Ph-like leukemias because of the exciting therapeutic relevance for highly resistant BCP-ALL. Translation to the clinic is likely to be faster with ‘ABL pathway’ ALLs, as TKIs are already routinely used for therapy of BCR-ABL1 ALL. Preclinical studies [13▪▪,15▪▪] and two case reports of complete remission of resistant ALLs with EBF1-PDGFRB fusions [56▪,57▪] treated with a combination of TKIs and chemotherapy are encouraging. Similarly to BCR-ABL1, it is unlikely that TKI single therapy will be effective. As the ‘ABL pathway’ lesions are so diverse and rare, a clinical trial is unlikely. It seems reasonable to enroll every such patient on an ongoing clinical trial for BCR-ABL1 ALL. Specific diagnosis is important, as there were no responses of Ph negative highly resistant ALLs enrolled in the recently published Dasatinib pediatric phase I/II trial [8].

The therapeutic approach to the JAK pathway BCP-ALLs is less clear. JAK inhibitors, for example, ruxolitinib the dual JAK1/JAK2 inhibitor, are approved for the treatment of myelofibrosis, but the experience in ALL is limited. A preclinical study of leukemia xenografts has demonstrated only transient partial responses of CRLF2 leukemias but dramatic responses of xenografts with JAK2 fusion [58▪]. This may be explained by a wider signaling impact of receptor abnormalities compared with a direct activation of JAK2 by a fusion translocation. Indeed, suppression of the mammalian target of rapamycin pathway, that is activated downstream to IL7R/CRLF2 [16▪] (Fig. 1), by the currently available drug rapamycin was effective in eliminating all xenografts with either CRLF2 expression or JAK fusions [58▪]. Alternatively, additional molecular events in the leukemic cells, such as the loss of Ikaros, and not CRLF2 may be ‘driving’ the resistance to JAK inhibitors [59▪].

As experience with JAK inhibitors is growing for the treatment of myeloproliferative neoplasms, so is the research of resistance mechanisms and the approaches to overcome resistance. HSP90 inhibitors, B-cell CLL/lymphoma 2 (BCL2) antagonists and novel conformation independent JAK2 inhibitors are being investigated as potential drugs for highly resistant JAK-STAT-driven ALLs [60▪,61▪,62].

It is important to stress that even in the absence of targeted therapy the majority of the Ph-like ALLs, especially the CRLF2 positive childhood ALLs, are cured by current chemotherapies. The challenge is, therefore, to diagnose BCP-ALLs resistant to current therapy that may respond to JAK or ABL inhibitors.

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With the exception of CRLF2 expressing ALLs, there are currently no standards for the diagnosis of Ph-like BCP-ALLs. The presence of about 100 different fusion genes (C. Mullighan, personal communication) poses a significant diagnostic challenge. Yet, diagnosis is important because of the therapeutic potential of available drugs. Without standards, the suggestions here represent my ‘current opinion’ (Table 2).

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The diagnosis of CRLF2 ALLs is relatively straightforward and is in the process of being incorporated into most childhood leukemia protocols. As CRLF2 is normally not expressed in B cells, CRLF2 antibody has been added to the diagnostic antibody panel for immunophenotyping of BCP-ALL. As P2RY8-CRLF2 fusion was reported to inflict worse prognosis than IgH translocations [63–65], fluorescent in-situ hybridization, PCR, multiplex ligation-dependent probe amplification [66] or genomic arrays can be performed to identify the genomic aberration causing CRLF2 expression.

For detection of other genetic lesions characterizing Ph-like ALL, patients may be selected based on the absence of the typical ALL genetic lesions and on resistance to initial therapy (e.g. high minimal residual disease at the end of induction).

Several diagnostic options could potentially be applied for such patients:

  1. Analysis of expression of specific genes – both the Children's Oncology Group and several central laboratories of the European childhood leukemia groups are testing panels of genes whose expression characterizes Ph-like or BCR-ABL1-like ALLs. Currently, however, it is unclear if they identify the same population at risk [67]. Moreover, the mere identification of a ‘BCR-ABL1 like’ gene expression does not provide therapeutic information regarding potential response to ABL or JAK TKIs.
  2. Phospho flow-cytometry: the technique measures level of phosphorylation of several proteins, such as STAT5 and CRKL, targets of JAK2 or ABL, respectively, before and after exposure to TKIs [13▪▪,68▪,69▪]. The advantage of this approach is in its potential predictive power for response to TKIs, thus bypassing the need for diagnosis of the specific genetic lesion.
  3. Cytogenetic techniques – including karyotype analysis and fluorescent in-situ hybridization with probes designed to detect IgH, PDGRFRB, ABL1, ABL2 and JAK2. Such probes (not all are available commercially) can detect the majority of rearranged genes and, similarly to phospho-flow cytometry, are informative for therapeutic decisions.
  4. Molecular approaches – either by multiplex PCR or targeted sequencing of the approximately all fusion genes already identified. Eventually, this may be the simplest diagnostic approach.

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The discovery that a significant proportion of high-risk BCP-ALLs is caused by activation of ABL or JAK kinases is exciting because it suggests that targeted therapy with TKIs may be relevant beyond the Philadelphia positive leukemias. As these drugs are already approved for clinical use, reliable diagnostic assays are urgently needed. Further research on the mechanisms by which IKZF1 deletions cooperate with activated JAK or ABL kinases in leukemogenesis could lead to novel-targeted therapeutics for both pathways.

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S.I. apologizes for lack of citations of many relevant references that were published prior to the last 2 years because of the policy of Current Opinons. S.I. thanks Ifat Geron for her assistance in drawing the figure. S.I. is indebted to all his laboratory members contributing to discoveries mentioned in this review. Funding of this work was provided by the Israel Science Foundation Legacy and ICORE programs, Children with Cancer (UK), Swiss Bridge Foundation, WLBH Foundation, Waxman Cancer Research Foundation, US–Israel Binational Science Foundation and Israel Cancer Research Foundation.

Limited research support from Pfizer Inc.

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Conflicts of interest

No conflicts of interest.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

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1▪. Greaves M. Janet Rowley (1925–2013). Science. 2014; 343:626

A concise review of the contribution of Dr Rowley, who recently passed away, to leukemia cytogenetics.

2▪. Schultz KR, Carroll A, Heerema NA, et al. Long term follow-up of imatinib in pediatric philadelphia chromosome-positive acute lymphoblastic leukemia: children's oncology group study AALL0031. Leukemia. 2014; [Epub ahead of print]

Long-term follow-up of a ground breaking phase II study incorporating imatinib to the treatment of childhood BCR-ABL1 ALL demonstrating 70% long-term disease-free survival and the possibility of omitting the need for hematopoietic stem cell transplantation (HSCT).

3▪▪. Biondi A, Schrappe M, De Lorenzo P, et al. Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study. Lancet Oncol. 2012; 13:936–945.

The first randomized pediatric trial demonstrating the efficacy of adding imatinib to chemotherapy of children with Philadelphia positive ALL.

4▪. Tanguy-Schmidt A, Rousselot P, Chalandon Y, et al. Long-term follow-up of the imatinib GRAAPH-2003 study in newly diagnosed patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: a GRAALL study. Biol Blood Marrow Transplant. 2013; 19:150–155.

Long-term follow-up of a trial for adults with Philadelphia positive ALL demonstrating marked improvement by the addition of imatinib but that HSCT is still needed.

5. Rives S, Camos M, Estella J, et al. Longer follow-up confirms major improvement in outcome in children and adolescents with Philadelphia chromosome acute lymphoblastic leukaemia treated with continuous imatinib and haematopoietic stem cell transplantation. Results from the Spanish Cooperative Study SHOP/ALL. Br J Haematol. 2013; 162:419–421.

6▪. Conter V, Valsecchi MG, Parasole R, et al. Childhood high-risk acute lymphoblastic leukemia in first remission: results after chemotherapy or transplant from the AIEOP ALL 2000 study. Blood. 2014; 123:1470–1478.

Intriguing report from the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL 2000 pediatric trial questioning the utility of HSCT for children with ALL in first remission.

7▪. Fielding AK, Rowe JM, Buck G, et al. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014; 123:843–850.

A study suggesting that the addition of imatinib prolonged survival of adults with Philadelphia positive ALL by enhancing the effect of HSCT.

8. Zwaan CM, Rizzari C, Mechinaud F, et al. Dasatinib in children and adolescents with relapsed or refractory leukemia: results of the CA180-018 phase I dose-escalation study of the Innovative Therapies for Children with Cancer Consortium. J Clin Oncol. 2013; 31:2460–2468.

9. Ottmann OG, Larson RA, Kantarjian HM, et al. Phase II study of nilotinib in patients with relapsed or refractory Philadelphia chromosome: positive acute lymphoblastic leukemia. Leukemia. 2013; 27:1411–1413.

10. Kantarjian HM, Cortes JE, Kim DW, et al. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood. 2014; 123:1309–1318.

11. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013; 369:1783–1796.

12▪▪. 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.

A landmark study that identified a subgroup of ‘BCR-ABL1 like’ ALLs with a similar gene expression and outcome to BCR-ABL1 positive ALLs.

13▪▪. 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.

A landmark study that identified the genetic lesions underlying Ph-like ALLs.

14. Loh ML, Zhang J, Harvey RC, et al. Tyrosine kinome sequencing of pediatric acute lymphoblastic leukemia: a report from the Children's Oncology Group TARGET Project. Blood. 2013; 121:485–488.

15▪▪. Li Y, Payne-Turner D, Harvey RC, et al. Genomic characterization and experimental modeling of BCR-ABL1-like acute lymphoblastic leukemia. Blood. 2013; 122:232

The most up-to-date genomic and functional analysis of Ph-like ALL.

16▪. Tal N, Shochat C, Geron I, et al. Interleukin 7 and thymic stromal lymphopoietin: from immunity to leukemia. Cell Mol Life Sci. 2014; 71:365–378.

A comprehensive up-to-date review of the role of CRLF2-IL7R-JAK-STAT pathway in ALL.

17▪. Yokoyama K, Yokoyama N, Izawa K, et al. In vivo leukemogenic potential of an interleukin 7 receptor alpha chain mutant in hematopoietic stem and progenitor cells. Blood. 2013; 122:4259–4263.

This study demonstrates that mutated IL7 receptor α is transforming in vivo, but the nature of the leukemia depends on the cell of origin.

18▪. Buitenkamp TD, Izraeli S, Zimmermann M, et al. Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group. Blood. 2014; 123:70–77.

The largest study of the biological and clinical characteristics of ALL in children with Down Syndrome. The study demonstrates that the high prevalence of CRLF2 aberrations has no prognostic significance in these children.

19. Shochat C, Tal N, Bandapalli OR, et al. Gain-of-function mutations in interleukin-7 receptor-{alpha} (IL7R) in childhood acute lymphoblastic leukemias. J Exp Med. 2011; 208:901–908.

20. Chapiro E, Radford-Weiss I, Cung HA, et al. Chromosomal translocations involving the IGH@ locus in B-cell precursor acute lymphoblastic leukemia: 29 new cases and a review of the literature. Cancer Genet. 2013; 206:162–173.

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. 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.

23. 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.

24. Graux C, Cools J, Melotte C, et al. Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Nat Genet. 2004; 36:1084–1089.

25. Montano-Almendras CP, Essaghir A, Schoemans H, et al. ETV6-PDGFRB and FIP1L1-PDGFRA stimulate human hematopoietic progenitor cell proliferation and differentiation into eosinophils: the role of nuclear factor-kappaB. Haematologica. 2012; 97:1064–1072.

26▪. Patterer V, Schnittger S, Kern W, et al. Hematologic malignancies with PCM1-JAK2 gene fusion share characteristics with myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1. Ann Hematol. 2013; 92:759–769.

A study summarizing a large series of hematological malignancies characterized by JAK2 fusions and abnormalities of the platelet-derived growth factor receptors and response to TKIs.

27. Aikawa Y, Katsumoto T, Zhang P, et al. PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced by MOZ-TIF2. Nat Med. 2010; 16:580–585.

28▪. 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.

A study demonstrating that fusion translocation involving the macrophage receptor CSF1R in imatinib-sensitive ALL.

29. Kasyapa C, Gu TL, Nagarajan L, et al. Phosphorylation of the SSBP2 and ABL proteins by the ZNF198-FGFR1 fusion kinase seen in atypical myeloproliferative disorders as revealed by phosphopeptide-specific MS. Proteomics. 2009; 9:3979–3988.

30. 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.

31. Atak ZK, Gianfelici V, Hulselmans G, et al. Comprehensive analysis of transcriptome variation uncovers known and novel driver events in T-cell acute lymphoblastic leukemia. PLoS Genet. 2013; 9:e1003997

32. Speck NA, Gilliland DG. Core-binding factors in haematopoiesis and leukaemia. Nat Rev Cancer. 2002; 2:502–513.

33. Mullighan CG, Goorha S, Radtke I, et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature. 2007; 446:758–764.

34▪. Olsson L, Castor A, Behrendtz M, et al. Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2100. Leukemia. 2014; 28:302–310.

A Scandinavian population-based study demonstrating the general poor prognosis of IKZF1-deleted ALLs.

35▪. Palmi C, Valsecchi MG, Longinotti G, et al. What is the relevance of Ikaros gene deletions as a prognostic marker in pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia? Haematologica. 2013; 98:1226–1231.

An analysis of AIEOP ALL trials demonstrating complex interactions between IKZF1 deletion and risk classification based on minimal residual disease. The study questions if IKZF1 deletions have general relevance for risk stratification of childhood ALL.

36▪. Dorge P, Meissner B, Zimmermann M, et al. IKZF1 deletion is an independent predictor of outcome in pediatric acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol. Haematologica. 2013; 98:428–432.

Analysis of a similar childhood treatment protocol to Palmi et al. arrives at the conclusion that IKZF1 deletion is an independent poor prognostic marker that may be utilized for risk stratification. The contrast between this study and the previous one may be related to more complex interactions with ethnicity and the percentage of Ph-like ALLs.

37▪. 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.

IKZF1 deletion is not a poor prognostic factor in the subtype of ALL with ERG deletion.

38▪. 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.

IKZF1 deletion is not a poor prognostic factor in the subtype of ALL with ERG deletion.

39▪▪. 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.

A study suggesting that the poor prognosis of the CRLF2 subtype of Ph-like ALLs may be caused by IKZF1 deletions.

40▪. van der Veer A, Zaliova M, Mottadelli F, et al. IKZF1 status as a prognostic feature in BCR-ABL1-positive childhood ALL. Blood. 2014; 123:1691–1698.

A study suggesting that IKZF1 deletion confers poor prognosis for BCR-ABL1 positive childhood ALL despite imatinib therapy.

41▪. Yamashita Y, Shimada A, Yamada T, et al. IKZF1 and CRLF2 gene alterations correlate with poor prognosis in Japanese BCR-ABL1-negative high-risk B-cell precursor acute lymphoblastic leukemia. Pediatr Blood Cancer. 2013; 60:1587–1592.

IKZF1 interacts with CRLF2 in conferring poor prognosis of childhood ALL.

42. Virely C, Moulin S, Cobaleda C, et al. Haploinsufficiency of the IKZF1 (IKAROS) tumor suppressor gene cooperates with BCR-ABL in a transgenic model of acute lymphoblastic leukemia. Leukemia. 2010; 24:1200–1204.

43▪▪. Heizmann B, Kastner P, Chan S. Ikaros is absolutely required for pre-B cell differentiation by attenuating IL-7 signals. J Exp Med. 2013; 210:2823–2832.

Ikaros deletion enhances IL-7 signaling and arrests differentiation. Explains the synergism between Ikaros deletion and activation of JAK-STAT pathway of ALL.

44▪▪. Joshi I, Yoshida T, Jena N, et al. Loss of Ikaros DNA-binding function confers integrin-dependent survival on pre-B cells and progression to acute lymphoblastic leukemia. Nat Immunol. 2014; 15:294–304.

Ikaros deletion enhances self-renewal and stroma adhesion of pre-B cells predisposing for pre-B leukemias. The first study to suggest a therapeutic approach for Ikaros-deleted leukemias, through inhibition of intergin signaling by FAK inhibitors.

45. Schwickert TA, Tagoh H, Gultekin S, et al. Stage-specific control of early B cell development by the transcription factor Ikaros. Nat Immunol. 2014; 15:283–293.

46. Gotoh A, Miyazawa K, Ohyashiki K, et al. Tyrosine phosphorylation and activation of focal adhesion kinase (p125FAK) by BCR-ABL oncoprotein. Exp Hematol. 1995; 23:1153–1159.

47. Xu H, Yang W, Perez-Andreu V, et al. Novel susceptibility variants at 10p12.31-12 2 for childhood acute lymphoblastic leukemia in ethnically diverse populations. J Natl Cancer Inst. 2013; 105:733–742.

48. Prasad RB, Hosking FJ, Vijayakrishnan J, et al. Verification of the susceptibility loci on 7p12.2, 10q21 2, and 14q11. 2 in precursor B-cell acute lymphoblastic leukemia of childhood. Blood. 2010; 115:1765–1767.

49. Trevino LR, Yang W, French D, et al. Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat Genet. 2009; 41:1001–1005.

50▪. Shah S, Schrader KA, Waanders E, et al. A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia. Nat Genet. 2013; 45:1226–1231.

In line with previous observations on somatic loss of PAX5 in ALL, this study demonstrates that germline haploinsufficiency of PAX5 predisposes to BCP-ALL.

51▪. Auer F, Ruschendorf F, Gombert M, et al. Inherited susceptibility to pre B-ALL caused by germline transmission of PAX5 c.547G>A. Leukemia. 2013; [Epub ahead of print]

In line with previous observations on somatic loss of PAX5 in ALL, this study demonstrates that germline haploinsufficiency of PAX5 predisposes to BCP-ALL.

52▪. Migliorini G, Fiege B, Hosking FJ, et al. Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype. Blood. 2013; 122:3298–3307.

GATA3 variants are associated with increased risk of childhood BCP-ALL belonging to the ‘Other B’ group.

53▪. Perez-Andreu V, Roberts KG, Harvey RC, et al. Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse. Nat Genet. 2013; 45:1494–1498.

GATA3 variants are associated with increased risk of childhood Ph-like BCP-ALL.

54▪. Walsh KM, de Smith AJ, Chokkalingam AP, et al. GATA3 risk alleles are associated with ancestral components in Hispanic children with ALL. Blood. 2013; 122:3385–3387.

This study is important as it demonstrates the confounding factor of ethnicity. Both GATA3 high-risk alleles and Ph-like ALL are more common in Hispanic children.

55▪. Louria-Hayon I, Frelin C, Ruston J, et al. Lnk adaptor suppresses radiation resistance and radiation-induced B-cell malignancies by inhibiting IL-11 signaling. Proc Natl Acad Sci U S A. 2013; 110:20599–20604.

A study suggesting a novel mechanism for the association between loss of SH2B3 and ALL.

56▪. 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.

A case of EBF1-PFGFRB Ph-like ALL responding to TKIs.

57▪. 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.

A case of EBF1-PFGFRB Ph-like ALL responding to TKIs.

58▪. 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.

A preclincial trial with xenografts of JAK-STAT Ph-like ALLs demonstrating variable activity of JAK inhibitors and excellent activity of mammalian target of rapamycin inhibitors.

59▪. Morak M, Attarbaschi A, Fischer S, et al. Small sizes and indolent evolutionary dynamics challenge the potential role of P2RY8-CRLF2-harboring clones as main relapse-driving force in childhood ALL. Blood. 2012; 120:5134–5142.

A provocative study, that requires independent confirmation, suggesting that P2RY8-CRLF2 is often present in leukemic subclones and does not drive relapse.

60▪. Waibel M, Solomon Vanessa, Knight DA, et al. Combined targeting of JAK2 and Bcl-2/Bcl-xL to cure mutant JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitors. Cell Rep. 2013; 5:1047–1059.

Inhibition of BCL2/BCL2-Like 1 (BCL-XL) maybe required in addition to JAK inhibitors for cure of JAK-driven leukemias.

61▪. Weigert O, Lane AA, Bird L, et al. Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition. J Exp Med. 2012; 209:259–273.

HSP90 inhibition could overcome the resistance to JAK inhibitors.

62. Koppikar P, Bhagwat N, Kilpivaara O, et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature. 2012; 489:155–159.

63. Palmi C, Vendramini E, Silvestri D, et al. Poor prognosis for P2RY8-CRLF2 fusion but not for CRLF2 over-expression in children with intermediate risk B-cell precursor acute lymphoblastic leukemia. Leukemia. 2012; 26:2245–2253.

64. Moorman AV, Schwab C, Ensor HM, et al. IGH@ translocations, CRLF2 deregulation, and microdeletions in adolescents and adults with acute lymphoblastic leukemia. J Clin Oncol. 2012; 30:3100–3108.

65. Cario G, Zimmermann M, Romey R, et al. Presence of the P2RY8-CRLF2 rearrangement is associated with a poor prognosis in nonhigh-risk precursor B-cell acute lymphoblastic leukemia in children treated according to the ALL-BFM 2000 protocol. Blood. 2010; 115:5393–5397.

66. Schwab CJ, Jones LR, Morrison H, et al. Evaluation of multiplex ligation-dependent probe amplification as a method for the detection of copy number abnormalities in B-cell precursor acute lymphoblastic leukemia. Genes Chromosomes Cancer. 2010; 49:1104–1113.

67. Hunger SP, Baruchel A, Biondi A, et al. The thirteenth international childhood acute lymphoblastic leukemia workshop report: La Jolla, CA, USA December 7-9. Pediatr Blood Cancer. 2013; 60:344–348.

68▪. Hasegawa D, Bugarin C, Giordan M, et al. Validation of flow cytometric phospho-STAT5 as a diagnostic tool for juvenile myelomonocytic leukemia. Blood Cancer J. 2013; 3:e160

A study demonstrating the clinical utility of phospho-flow cytometry.

69▪. 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.

A phospho-flow cytometry study demonstrating the consequences of CRLF2 expression in primary ALL cells. These observations can be translated into diagnostics.


acute lymphoblastic leukemia; BCR-ABL1; CRLF2; interleukin-7 receptor; Janus kinase 2; Philadelphia like

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins


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