Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation

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.).

Figures

Figure 1.

ASXL1 mutations in a cohort of GATA2 deficiency patients. (A) Diagram of the 3′-terminal two exons of the ASXL1 gene (NC_000020 REGION: 30946147.31027122) indicating the regions sequenced and the mutations found in this cohort of patients. An (*) indicates a novel mutation identified in this study. (B) Discordance in ASXL1 mutations between two sets of sisters; each sister had the identical GATA2 mutation. In kindred 1.II, the patients had different ASXL1 genotypes, with sister A displaying a normal sequence at the locus where sister B had a c.1192C>T mutation. Kindred 33.III shows sister A (patient 23) with an ASXL1 c.1900del23 mutation while sister B (patient 24) has no ASXL1 mutation. The International Union of Pure and Applied Chemistry (IUPAC) notation is used to designate nucleotide sequence. (C) Example of disease progression and ASXL1 mutation profile in patient 18. Sequence traces show patient 18 with ASXL1 c.1934insG mutation prior to bone marrow transplantation. This mutation was not detectable after a non-myeloablative transplant from her normal sibling, re-appeared at relapse, and became undetectable again after a second, myeloablative transplant from the same donor. Kindred designations are listed in Online Supplementary Table S2.

Figure 2.

Biometric parameters of GATA2 deficiency patients. (A) Summary of the ASXL1 mutation status, clinical diagnosis, and biometric characteristics of the 48 patients in this study. Patients with ASXL1 mutations are grouped together, followed by patients without ASXL1 mutations. Within each group, patients’ samples are shown in chronological order of analysis, as listed in Table 1 and Online Supplementary Table S2. A yellow box indicates unfavorable cytogenetics, with “7” or “8” indicating the presence of monosomy 7 or trisomy 8, respectively. A gray box indicates information that is not available. (B) Patients’ age at sample collection for patients with and without ASXL1 mutations. Means and standard errors are shown for each data set. There is no statistical difference between the means (P=0.81) or the variance (P=0.26). (C) Percentages of male and female patients with an ASXL1 mutation (colored boxes) and the percentages without a mutation (gray boxes) out of the total number of patients of each gender.