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Mechanisms of leukemic transformation in congenital neutropenia

Link, Daniel C.

Current Opinion in Hematology: January 2019 - Volume 26 - Issue 1 - p 34–40
doi: 10.1097/MOH.0000000000000479
MYELOID BIOLOGY: Edited by David C. Dale

Purpose of review The development of a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in patients with congenital neutropenia is now the major cause of mortality. Treatment options are limited and there are no effective prevention strategies. This review focuses on mechanisms of leukemic transformation in severe congenital neutropenia (SCN) and Shwachman–Diamond syndrome (SDS), the two most common types of congenital neutropenia.

Recent findings AML/MDS that develops in the setting of congenital neutropenia has distinct molecular features. Clonal hematopoiesis because of TP53 mutations is seen in nearly 50% of patients with SDS, but is not seen in patients with SCN. Accordingly, there is a very high frequency of TP53 mutations in AML/MDS arising in the setting of SDS but not SCN. The rate of mutation accumulation in hematopoietic stem cells (HSCs) from patients with congenital neutropenia is not increased.

Summary Both HSC cell-intrinsic and noncell-intrinsic changes contribute to the development of clonal hematopoiesis in congenital neutropenia and likely accounts for the high rate of leukemic transformation. In SCN, the persistently high levels of granulocyte colony-stimulating factor drive expansion of HSCs carrying truncation mutations of CSF3R. In SDS, impaired ribosome biogenesis induces p53-mediated growth inhibition and drives expansion of HSCs carrying TP53 mutations.

Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA

Correspondence to Daniel C. Link, MD, Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8007, St. Louis, MO 63110, USA. Tel: +1 314 362 8771; fax: +1 314 362 9333; e-mail:

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Bone marrow failure syndromes are characterized by a deficiency of one or more hematopoietic lineage. A common feature of both congenital and acquired forms of bone marrow failure is an increased risk to develop acute myeloid leukemia (AML) or a myelodysplastic syndrome (MDS). Significantly increased risks of AML/MDS have been reported in Fanconi anemia, dyskeratosis congenita, Diamond–Blackfan syndrome, Shwachman–Diamond syndrome (SDS), and severe congenital neutropenia (SCN). Treatment options for patients with bone marrow failure syndromes who develop AML/MDS are limited, and there are no reliable biomarkers that predict progression. Thus, there is a pressing clinical need to develop strategies to prevent, diagnose early, and treat AML/MDS in patients with bone marrow failure syndromes. This review will focus on mechanisms of leukemic transformation in the two most common types of congenital neutropenia, SCN and SDS.

Box 1

Box 1

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SCN is a congenital bone marrow failure syndrome characterized by severe neutropenia present from birth, an arrest of myeloid differentiation at the promyelocyte/myelocyte stage, and frequent infections. SCN is a genetically heterogeneous disorder. Mutations of ELANE are the most common cause of SCN, accounting for approximately 50% of cases [1–3]. Other genes mutated in SCN include HAX1, G6PC3, SRP54, GFI1, CSF3R, VPS45, WAS, JAGN1, and TCIRG1; the genetic cause of approximately 30% of SCN cases remains unknown [4,5]. As expected given the genetic heterogeneity, diverse mechanisms of disease pathogenesis have been proposed for SCN. Although controversial, there is evidence that mutated ELANE (which encodes for neutrophil elastase) results in the production of misfolded neutrophil elastase, which in turn, induces the unfolded protein response and apoptosis in promyelocytes [6,7]. Treatment with granulocyte colony-stimulating factor (G-CSF) is the standard of care for SCN, as it increases the level of circulating neutrophils and reduces infection-related mortality [8]. Indeed, since the widespread use of G-CSF, the major cause of mortality in SCN is the development of AML/MDS. The French Neutropenia Registry reported a cumulative incidence of MDS or AML in patients with SCN of 10.8% at 20 years of age [9]. A prospective study of 374 patients with SCN on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry showed that the cumulative risk of developing AML/MDS is 22% after 15 years on G-CSF [10]. Moreover, no plateau in the incidence of AML or MDS was observed, suggesting that the cumulative risk of progression may be even higher. Patients requiring higher doses of G-CSF and who have a reduced neutrophil response to G-CSF have the highest rate of leukemic transformation [10,11]. Of note, AML or MDS has been reported in SCN associated with mutations in ELANE, HAX1, G6PC3, and WAS [12,13].

AML/MDS arising in the setting of SCN is associated with distinct molecular features compared with de novo AML/MDS (Table 1). Secondary AML/MDS in patients with SCN is frequently associated with monosomy 7 and abnormalities of chromosome 21 [14–16]. In the largest published series to date, candidate gene sequencing of 15 genes in 30 cases of SCN-AML/MDS showed that 27 (90%) had truncation mutations of CSF3R, encoding the G-CSF receptor (G-CSFR), and 19 (63%) had mutations in RUNX1 [17▪▪]. These data are consistent with prior studies showing that truncations mutations of CSF3R are present in approximately 80% of cases of SCN-AML/MDS [18,19]. In contrast, monosomy 7, RUNX1, and CSF3R mutations are relatively uncommon in de novo AML [18]. Studies reporting results of whole genome or exome sequencing of SCN-AML/MDS are limited, with only a single case reported [20]. Thus, the full spectrum of somatic mutations contributing to leukemic transformation in SCN has not been fully characterized.

Table 1

Table 1

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Truncation mutations of the CSF3R were first identified in a patient with SCN who developed AML [21]. The great majority of these mutations are nonsense mutations that truncate the cytoplasmic domain of the G-CSFR. Of note, the truncation mutations are distinct from the transmembrane proximal missense CSF3R mutations that are associated with chronic neutrophilic leukemia [22,23] or the extracellular loss-of-function biallelic CSF3R mutations that are a rare cause of SCN [24]. The truncated G-CSFR found in SCN, whereas remaining dependent on G-CSF, displays enhanced signaling because of impaired internalization and disturbed lysosomal targeting [25–28]. Transgenic mice carrying targeted mutations of the Csf3r reproducing these truncation mutations show that it results in enhanced myeloid progenitor proliferation, due at least in part, to increased signal transducer and activator of transcription 5 (STAT5) activation [29,30]. In the largest published series, CSF3R truncation mutations were detected in 43 of 125 (34%) patients with SCN without evidence of leukemic transformation versus 18 of 23 (78%) with MDS/AML, monosomy 7, or other clonal hematopoietic malignancy [31,32]. Interestingly, CSF3R mutations were detected in some patients before starting G-CSF. Serial analysis of CSF3R mutations over time show that, in some cases, CSF3R mutations are present before the development of MDS/AML [17▪▪,20,33]. Of note, CSF3R mutations can persist for years without the development of MDS/AML and can occasionally spontaneously disappear, limiting their usefulness as a biomarker for the development of AML/MDS [34,35].

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The accumulation of mutations in hematopoietic stem cells (HSCs) with age results in the production of a genetically heterogeneous cell population, with each HSC possessing its own unique set of private mutations [36]. HSCs that acquire somatic mutations that confer a competitive fitness advantage relative to their normal counterparts may clonally expand, resulting in the presence of clonal hematopoiesis in healthy individuals [37–39]. Factors that increase the rate at which mutations accumulate in HSCs may increase the frequency of clonal hematopoiesis and ultimately MDS/AML. The common mutations causing SCN are not known to be directly involved in DNA repair, suggesting the possibility that noncell autonomous mechanisms may contribute to the high rate of leukemic transformation. For example, G-CSF expression is induced by neutropenia and may increase the rate at which HSCs accumulate mutations by inducing their replication and/or by inducing reactive oxygen species [40,41]. To test this possibility, we measured the mutation burden in individual hematopoietic stem/progenitor cells (HSPCs) in patients with SCN [42▪▪]. Surprisingly, the number of somatic mutations in the exome of HSPCs from patients with ELANE-mutated SCN (3.6 ± 1.2) was similar to that observed in age-matched healthy controls (3.9 ± 0.4). Thus, current data suggest that the rate of mutation accumulation in HSCs with age is not increased in patients with SCN.

There is emerging evidence that hematopoietic stressors may select for HSCs carrying certain mutations, leading to their clonal expansion. For example, recent studies show that exposure to chemotherapy results in the expansion of HSC clones carrying TP53 or PPM1D mutations [43–45]. Patients with SCN (or other congenital neutropenia syndromes) are often exposed to repeated bouts of infection, resulting in the production of inflammatory cytokines, including G-CSF, which might contribute to the development of clonal hematopoiesis. We recently reported the frequency of clonal hematopoiesis in 41 patients with SCN [42▪▪]. As expected, clonal hematopoiesis because of truncation mutations of CSF3R were frequently detected in patients with SCN but not in healthy controls or patients with SDS. Importantly, no increase in clonal hematopoiesis because of any other mutation was detected.

Together, these data suggest a model of leukemogenesis in which the very high level of G-CSF present in patients (either through endogenous production or pharmacologic administration) is driving the expansion of HSCs carrying CSF3R mutations (Fig. 1). This is consistent with data showing that expression of a truncated G-CSFR in mice confers a clonal advantage to HSCs in a G-CSF-dependent fashion [24]. Although clearly not sufficient to induce AML/MDS, there is strong evidence that CSF3R truncation mutations contribute to leukemogenesis, including the following: their high prevalence in SCN-AML/MDS; their ability to cooperate with the Promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA) oncogene in mice to induce AML [46]; and the observation that increased G-CSFR signaling because of transmembrane proximal missense CSF3R mutations cause chronic neutrophilic leukemia. Transformation to AML/MDS requires the acquisition of additional somatic mutations, which in patients with SCN commonly includes mutations of RUNX1 and alterations of chromosome 7 [17▪▪].



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SDS is a recessive disorder characterized by hematopoietic abnormalities, exocrine pancreatic insufficiency, and skeletal abnormalities. Neutropenia is present in the majority of patients with variable severity and it may be intermittent [47]. Anemia and thrombocytopenia are present in more than a third of patients. SDS is caused in the great majority of cases by biallelic mutations of SBDS [48]. The SBDS protein facilitates the release of eukaryotic translation initiation factor 6 (EIF6) from the pre60S ribosome, allowing for the joining of 60S and 40S ribosome subunits to generate translationally active 80S ribosome [49]. Consequently, the loss-of-function SBDS mutations present in patients with SDS are associated with impaired ribosome biogenesis. There also is evidence implicating SBDS in the formation and stabilization of mitotic spindles [50]. Similar to SCN, patients with SDS have a marked propensity to develop MDS or AML. The French Severe Chronic Neutropenia Study Group reported a rate of transformation to AML/MDS of 18.8% at 20 years and 36.1% at 30 years based on a cohort of 55 patients with SDS [9]. The Canadian Inherited Marrow Failure Registry reported that nine of 40 patients with SDS developed AML/MDS or a clonal cytogenetic abnormality [51▪]. Consistent with these findings, the Severe Chronic Neutropenia International Registry reported a crude rate of transformation of AML/MDS 1% per year based on a cohort of 22 patients with SDS [11]. In contrast, none of the 17 patients with SDS in the NIH registry developed AML/MDS, which may reflect the relatively young (median age of 14) in this cohort [52].

AML/MDS arising in the setting of SDS also is associated with distinct molecular features. Lindsley et al. [53▪] in their study of patients with MDS identified seven patients carrying biallelic SBDS mutations. Interestingly, only two of these patients carried a diagnosis of SDS, suggesting that this syndrome may be underdiagnosed. Strikingly, mutations of TP53 were detected in all seven cases of SDS-MDS versus an overall frequency of TP53 mutations in primary MDS of only 14%. Myers et al. [54] recently reported clinical features of 37 patients with SDS who developed MDS or AML. Complex cytogenetic abnormalities, often involving chromosome 7, were identified in eight of nine cases with SDS-AML and five of six SDS patients with high-grade MDS. It is important to note that isochromosome 7q and del(20q) are common cytogenetic abnormalities associated with SDS that can persist for years and are not clearly linked to the development of AML/MDS [55,56].

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We recently reported that clonal hematopoiesis because of TP53 mutations was present in 13 of 27 (48%) of patients with SDS without AML/MDS or clonal cytogenetic abnormality [42▪▪]. In contrast, no TP53 mutations were detected in healthy controls or patients with SCN. As noted already, mutations of SBDS, which are present in the great majority of cases of SDS, result in impaired ribosome biogenesis [57–59]. There is evidence that ribosome biogenesis stress induces p53 expression, which in turn, results in growth arrest. For example, impaired ribosome biogenesis in Diamond–Blackfan Syndrome or 5q syndrome (which have impaired ribosome biogenesis because of mutations of ribosomal protein S12 (RPS14) or RPS19, respectively) results in increased p53 expression that contributes to the impaired erythropoiesis in these disorders [60–64]. Increased p53 expression also has been identified in hematopoietic cells from patients with SDS or in Sbds-deficient murine hematopoietic cells [59,65]. Together, these observations suggest a model in which elevated p53 expression because of ribosome biogenesis stress in SDS HSCs results in impaired HSC growth and/or survival (Fig. 2). Mutations of TP53 in HSCs are predicted to attenuate this growth arrest, resulting in their selective expansion in patients with SDS. Perhaps even more worrisome, this model predicts that continued ribosome biogenesis stress in TP53-mutated HSCs would provide a clonal advantage to HSCs that inactivate the second TP53 allele. We suggest that the early accumulation of TP53 mutations in HSPCs is the major reason for the increased risk of developing MDS/AML in patients with SDS. Consistent with this conclusion, a recent study showed that seven of seven (100%) of cases of MDS arising in the setting of SDS carried TP53 mutations [53▪].



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The development of AML/MDS is a major cause of mortality in patients with congenital neutropenia. Once AML/MDS develops, the only potentially curative therapy is allogenic HCT (alloHCT) transplantation. However, alloHCT is associated with significant treatment-related morbidity and mortality and risk of AML/MDS relapse. As CSF3R truncation mutations remain dependent on G-CSF, our model of leukemogenesis predicts that therapeutic approaches in patients with SCN that eliminate or reduce the need for G-CSF would substantially lower the risk of developing AML/MDS. Moreover, as the data suggest there is no cell-intrinsic increased risk of leukemic transformation in SCN, minimal conditioning regimens resulting in mixed donor chimerism after alloHCT transplant are predicted to have a very low risk to develop myeloid malignancy. This is consistent with a recent report by the European which showed that no myeloid malignancies occurred after alloHCT for 136 patients with SCN [66]. With respect to SDS, our model predicts that therapeutic strategies that alleviate ribosome biogenesis stress in SDS HSCs would prevent the emergence of TP53-mutated clonal hematopoiesis and reduce the risk of transformation to AML/MDS. Moreover, this model predicts that SDS HSCs would be at a competitive disadvantage compared with normal HSCs. Thus, minimal conditioning regimens for alloHCT should be sufficient to establish full donor chimerism in patients with SDS.

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I thank patients and their families with congenital neutropenia for their time and willingness to share tissue samples with researchers.

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Financial support and sponsorship

This work was supported by NIH grants P50CA171963 and P01CA194552.

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Conflicts of interest

There are 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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acute myeloid leukemia; granulocyte colony-stimulating factor receptor; granulocyte colony-stimulating factor; myelodysplastic syndrome; severe congenital neutropenia; Shwachman–Diamond syndrome; TP53

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