Abstract
Inherited or sporadic heterozygous mutations in the transcription factor GATA2 lead to a clinical syndrome characterized by non-tuberculous mycobacterial and other opportunistic infections, a severe deficiency in monocytes, B cells and natural killer cells, and progression from a hypocellular myelodysplastic syndrome to myeloid leukemias. To identify acquired somatic mutations associated with myeloid transformation in patients with GATA2 mutations, we sequenced the region of the ASXL1 gene previously associated with transformation from myelodysplasia to myeloid leukemia. Somatic, heterozygous ASXL1 mutations were identified in 14/48 (29%) of patients with GATA2 deficiency, including four out of five patients who developed a proliferative chronic myelomonocytic leukemia. Although patients with GATA2 mutations had a similarly high incidence of myeloid transformation when compared to previously described patients with ASXL1 mutations, GATA2 deficiency patients with acquired ASXL1 mutation were considerably younger, almost exclusively female, and had a high incidence of transformation to a proliferative chronic myelomonocytic leukemia. These patients may benefit from allogeneic hematopoietic stem cell transplantation before the development of acute myeloid leukemia or chronic myelomonocytic leukemia. (ClinicalTrials.gov identifier NCT00018044, NCT00404560, NCT00001467, NCT00923364.)Introduction
Recently, four groups described a new human disease syndrome, termed GATA2 deficiency, resulting from heterozygous germline or sporadic mutations in the transcription factor GATA2.1–4 Each group approached this syndrome from a distinct clinical perspective resulting in four different names for the same syndrome: autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC);3,5 dendritic cell, monocyte, B and NK lymphoid (DCML) deficiency;1 Emberger syndrome with lymphedema and monosomy 7;4 and familial myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML).2 The constellation of disease manifestations for GATA2 deficiency includes: (i) human papillomavirus, non-tuberculous mycobacterial and other opportunistic infections; (ii) severe deficiency of monocytes, dendritic cells, B cells, and NK cells in the peripheral blood, (iii) sporadic or autosomal dominant inheritance; (iv) the propensity to transform from a hypocellular MDS to AML or chronic myelomonocytic leukemia (CMML).
The late and variable tendency for GATA2 deficiency patients to develop AML/CMML invokes the Knudsen hypothesis of multiple de novo mutations driving progression to cancer.6,7 However, it has not been determined whether the genetic lesions associated with the pathogenesis of de novo AML are the same as those driving leukemic transformation when the initiating “hit” is discrete, as in GATA2-associated AML. Mutations in ASXL1 (Additional sex combs-like 1 gene) have been associated with the transformation of MDS to AML, and particularly, CMML.8–11 Transformation from MDS to AML/CMML is also common among GATA2 deficiency patients. Furthermore, ASXL1 mutations were reported in two cousins with GATA2 mutations.12 We, therefore, investigated whether ASXL1 mutations were a common “second hit” among GATA2 deficiency patients, and whether this correlated with leukemic transformation. ASXL1, the mammalian homolog of the Drosophila additional sex combs gene, is an essential component of two distinct chromatin-modifying complexes and is expressed in hematopoietic cell lineages.13
We identified mutations in ASXL1 in 14/48 (29%) of GATA2 deficiency patients, including four patients who progressed to CMML. We found notable differences in the clinical and biometric features in GATA2 deficiency patients with MDS/AML and patients with MDS/AML without preceding GATA2 mutations.
Methods
ASXL1 exons 12 and 13 (NCBI: NM_015338) were analyzed by direct sequencing in 48 patients with GATA2 mutations. A polymerase chain reaction (PCR) was used to amplify a 4,287 bp segment of ASXL1 with several overlapping primer sets (Online Supplementary Table S1). Substrate DNA was isolated from mononuclear and granulocyte cell preparations from peripheral blood or bone marrow aspirates using Gentra Puregene or DNeasy Blood & Tissue Kits (QIAGEN Sciences, Germantown, MD, USA), or from extracts prepared from microscope slides of unfixed, unstained bone marrow aspirates using the Epicentre BuccalAmp DNA Extraction Kit (Madison, WI, USA) (Online Supplementary Table S2). The PCR were done with AccuPrime Taq DNA Polymerase High Fidelity (Life Technologies, Grand Island, NY, USA) using the manufacturer’s recommended conditions with 30 ng of substrate DNA and 35 amplification cycles, with the following amplification parameters: 94°C for 20 seconds; 58°C for 30 seconds, and 68°C for 60 seconds/kilobase of amplified product. The p.G646Wfs*12insG mutation was verified first by repeating the PCR using two different primer sets (Online Supplementary Table S1: primers 1/4, primers 2/3), then by repeating the reactions with different polymerase enzymes [AccuPrime Pfx (Life Technologies, Grand Island, NY, USA), DreamTaq (Thermo Scientific, Pittsburgh, PA, USA)] using the manufacturers’ recommended conditions. PCR products were purified using the QIAquick PCR Purification Kit (QIAGEN Sciences, Germantown, MD, USA) and sequenced using ABI 3130XL and 3730 fluorescence-based sequencers. Sequences were analyzed with MacVector, version 12.0 (MacVector, Inc, Cary, NC, USA). Mutations were confirmed with independent PCR with separate primer sets. Statistical analyses were done with GraphPad Prism, version 5.0 (GraphPad Software, Inc., La Jolla CA, USA). The clinical protocols under which these studies were undertaken were reviewed and approved by the Institutional Review Board of the National Institutes of Health, Clinical Research Center. Patients in this study were enrolled in National Institutes of Health/National Institute of Allergy and Infectious Diseases ClinicalTrials.gov Identifier: NCT00018044, NCT00404560, NCT00001467, and National Cancer Institute ClinicalTrials.gov Identifier: NCT00923364.
Results and Discussion
We screened 48 patients with inherited GATA2 mutations to determine the incidence of somatic ASXL1 mutations. A schematic of the ASXL1 region that was sequenced, which contains ~90% of known ASXL1 mutations (COSMIC, v6614), and the position of the mutations found in this study, are shown in Figure 1A. Sequence variations found in the Database of Single Nucleotide Polymorphisms (dbSNP) were not included as mutations (Online Supplementary Table S3). Somatic ASXL1 mutations were detected in 14/48 (29%) patients with GATA2 deficiency (Table 1). All of these mutations were heterozygous and located within exon 13. The ASXL1 mutations found among GATA2 deficiency patients were similar to mutations previously reported in MDS and AML patients,15 including five independent cases of the most frequently described ASXL1 mutation (p.G646Wfs*12insG). The p.G646Wfs*12insG mutation was previously reported in two cousins with a GATA2 mutation who had developed MDS.12 However, there has been concern over the validity of this particular mutation, with suggestions that it is a PCR artifact since it occurs immediately 3′ to an eight base poly G sequence.16 We confirmed this mutation by repeating the PCR at least three times for each positive sample (for patient 18, more than 12 times) with different primer pairs, and using different enzymes for amplification in the PCR (see Methods section). In each case, the mutation was consistently present in the positive samples, and was not observed in normal controls. Moreover, the presence of the mutation correlated with the clinical course in two patients (Figure 1C, Online Supplementary Figure S1). There were also three cases of the second most common ASXL1 mutation (p.E635fs*15del23) (COSMIC, v6614). These two mutations have been reported at similar rates in previous studies of AML and CMML.10,11,17–21 The remaining six mutations were found once each. Three of them were previously unreported: G652S, L817fs*1, and L866X. There was no correlation between the presence or type of somatic ASXL1 mutation and the specific germline GATA2 mutation; the eight different ASXL1 mutations were found in ten different GATA2 mutant backgrounds (Table 1).
Two pairs of sisters with the same GATA2 mutations had discordant ASXL1 genotypes (Figure 1B, Table 1). The first pair of sisters (kindred 1.II, patients 3 and 4) both progressed to CMML, but one had the somatic ASXL1 c.2077C>T mutation, and the other a possible c.1934insG mutation. In the second pair of sisters (kindred 33.III, patients 23 and 24), one had an ASXL1 mutation and MDS (patient 23), whereas the younger sister did not have either an ASXL1 mutation or MDS (patient 24).
The ASXL1 mutation was also followed through disease progression and treatment in two patients (Figure 1C). The c.1934insG mutation was detected in patient 18 prior to treatment, became undetectable following non-myeloablative hematopoietic stem cell transplantation, re-emerged with relapse, and became undetectable again following a second, myeloablative transplant. This re-appearance of an ASXL1 mutation upon relapse has also been seen in AML patients,18,20 indicating that it is a stable mutation. Patient 19 showed an increase in the mutation signal over time, which correlated with progression from MDS to a terminal, proliferative CMML (Online Supplementary Figure S1).
Several biological features characterized patients with GATA2 deficiency who harbored ASXL1 mutations (Figure 2A). ASXL1 mutations were found in four of five patients with GATA2 deficiency who developed CMML, consistent with the previously reported high incidence of ASXL1 mutations in CMML.9,10,21,22 Moreover, when Gelsi-Boyer et al.10,23 divided their group of patients into those with dysplastic (CMML-MD) and proliferative (CMML-MP) forms of CMML, ASXL1 mutations were present in 76% of CMML-MP cases versus 27% of CMML-MD cases. The CMML patients in this report all had CMML-MP. While ASXL1 mutations were prevalent in patients who developed CMML, the presence of an ASXL1 mutation was not a predictor for the development of MDS: 27/37 (73%) patients who developed MDS lacked ASXL1 mutations.
Several studies have shown that the average age of MDS/AML patients with ASXL1 mutations is higher than that of patients without an ASXL1 mutation.9,18–20,24,25 In general, ASXL1 mutations are also rare in pediatric AML.26,27 However, this was not seen in GATA2 deficiency patients. The average age of GATA2 deficiency patients with an ASXL1 mutation (35.8 ± 12.8 years old, range, 17–59 years old) was markedly younger than that of other MDS/AML groups, but not significantly different from that of GATA2 deficiency patients without an ASXL1 mutation (34.5±17.0 years old, range 10–78 years old) (t-test, P=0.81) (Figure 2B). Thus, although many gene mutations associated with MDS/AML correlate with age, the ASXL1 mutations described here, like previously reported FLT3-IDT mutations,28 are notable exceptions. Curiously, acquired GATA2 mutations in CEBPA-AML patients also occur in younger patients.29
ASXL1 mutations in previously described MDS/AML patients show a significant bias towards male patients (~70%) when averaged over several previous studies.11,18–21,25,30 In contrast, 13/14 (93%) of the GATA2 deficiency patients with ASXL1 mutations were female (Figure 2C). Moreover, four of the five GATA2 patients with CMML were female and had an ASXL1 mutation. The male CMML patient did not have an ASXL1 mutation, and the male patient with an ASXL1 mutation did not have CMML. Gender bias was not seen in the other biometric data analyzed here. Leukemic mutations in some chromatin modifiers show a modest clustering in female patients, but ASXL1, and its most frequently associated genes, SRSF2 and U2AF1, are more frequent in males.31
The basis for the gender bias observed here in GATA2 deficiency patients is unknown. However, GATA2 plays a role in the hormone-dependent recruitment of the androgen receptor to chromatin, and in this way, GATA2 influences the expression of androgen-dependent genes, while not being directly regulated by androgen.32 GATA2 is also over-expressed in aggressive, metastatic prostate cancers, and its expression affects the hormone-responsive growth of these cells.33 The significance of this in hematopoiesis and leukemia is not known, but the androgen receptor is expressed widely in the bone marrow in both males and females.34
Among MDS/AML patients, ASXL1 mutations are most commonly found in patients with International Prognostic Scoring System low/intermediate 1 risk or normal cytogenetics.11,15,19,24,26,35 Cytogenetics from 13 of the GATA2 deficiency patients with ASXL1-mutations showed a 46% incidence of unfavorable cytogenetics: monosomy 7 in two, monosomy 7 and trisomy 8 in two, one translocation t(1;22), and one chromosome 6 monosomy (Table 1, Figure 2A). The two GATA2 deficiency patients with ASXL1 mutations described by Bödör et al. also had monosomy 7.12 However, over 40% of the GATA2 deficiency patients (13/32) without ASXL1 mutations had monosomy 7 (4/32) or trisomy 8 (9/32). Thus, an abnormal karyotype was not more common among patients with ASXL1 mutations than those without the mutation. The high frequency of monosomy 7 and/or trisomy 8 among GATA2 deficiency patients makes it difficult to assess the relationship between ASXL1 mutation and these abnormal karyotypes.
Several studies have suggested that the presence of an ASXL1 mutation in MDS/AML patients is a predictor of rapid disease progression and poor overall survival.8,11,15,22,25,36,37 Among the GATA2 deficiency patients, 6/14 (43%) with an ASXL1 mutation did not survive the time period of this study. In contrast, the mortality rate was 4/34 (12%) for those without an ASXL1 mutation. Thus, our results are consistent with earlier reports that an ASXL1 mutations correlate with poor survival.
Mutations in the ASXL1 gene have become a common observation in hematopoietic malignancies, particularly in sporadic MDS and AML/CMML. The mutations that drive leukemogenesis generally fall into discrete categories of function, including transcription factors, epigenetic modifiers, splicing factors, and signal transduction pathways.7,38,39 Patients with GATA2 mutations usually have inherited or acquired a mutation in the first category of mutation, the GATA2 transcription factor. The ASXL1 mutation represents the second class of mutation, an epigenetic or chromatin modifier. Presumably, the patients who progress to AML and CMML have additional somatic mutations in the malignant myeloid clone.
This study indicates that mutations in ASXL1 in patients with mutations in GATA2 represent an important “second hit” in myeloid transformation, particularly to CMML. In this cohort of patients, mutations in ASXL1 indicate the need for close clinical follow-up and, potentially, allogeneic hematopoietic stem cell transplantation. Recently, we have initiated whole exome analysis on GATA2 deficiency patients to further define the pattern of genetic changes that influence the tempo and phenotype of myeloid transformation.
Acknowledgments
The authors would like to thank the patients and their families for providing research samples for these studies.
Footnotes
- The online version of this article has a Supplementary Appendix.
- Funding This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, and the Mark Hatfield Clinical Research Center.
- Authorship and Disclosures Information on authorship, contributions, and financial & other disclosures was provided by the authors and is available with the online version of this article at www.haematologica.org.
- Received April 24, 2013.
- Accepted September 27, 2013.
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