SUMMARY and DISCUSSION
The protein product of the GATA2 gene is a transcription factor with two DNA-binding zinc finger domains. This protein plays a significant role in the induction and expansion of hematopoietic stem cells (HSCs) during fetal development and in proliferation of HSCs in later life [6]. While the specific mechanisms of leukemogenesis in GATA2 deficiency are not completely understood, pathogenic mutations are thought to cause loss of one of the zinc finger domains present in GATA2, thereby inhibiting or altering its interactions with DNA [7, 8].
In this case, whole genome CGH+SNP microarray results were suggestive of a constitutional (germline) loss of 3q21.3, corresponding to the area of the chromosome containing the GATA2 gene (Figure 1F). Germline mutations in the GATA2 gene have been detected in up to 7% of pediatric MDS cases, reaching a prevalence of 72% in pediatric MDS with monosomy 7, as was present in our case [7]. The identification of germline mutations is a finding of particular significance for patients, as these mutations can be inherited and may be present in other family members.
Additional mutations were identified using next-generation sequencing in this case, including ETV6, EZH2, ASXL1, and SETBP1. ETV6 encodes a transcription factor which has an important role in regulation of hematopoiesis and whose alterations have been implicated in the development of several hematologic malignancies [9]. The products of the ASXL1 and EZH2 genes are involved in epigenetic regulation of stem cell differentiation via histone methylation, and mutations in these two genes are commonly seen in MDS [10]. SETBP1 codes for a proto-oncogene whose overexpression is frequently present in AML. The presence of SETBP1 mutation is also associated with mutations in ASXL1 and EZH2. Each of these mutations is independently associated with poor prognosis in MDS and/or AML [10, 11].
Conventional karyotyping can also be an important source of prognostic information, not only by identifying specific prognostically useful chromosomal abnormalities within a neoplasm, but also by demonstrating clonal evolution and/or the presence of subclones. Both clonal evolution and subclones are associated with progression of MDS to AML, as well as with poor prognosis for patients already diagnosed with AML [12]. In this case, two abnormal clones were detected on conventional karyotyping, one clone with monosomy 7 and a subclone with both monosomy 7 and trisomy 8.
Regarding treatment of MDS and AML, HSCT is the only curative therapy. HSCT may utilize a related donor, although in the case of a patient with a germline mutation, testing the relative for the presence of the same mutation should be considered, in order to avoid transplanting tissue with a similar potential for neoplastic transformation. In this case, however, the patient received a transplant from an unrelated donor. Following HSCT, overall survival rates in patients with germline GATA2 mutations are reportedly similar to those of patients without such mutations, although the incidence of transplant-related neurological toxicity and thrombotic events may be increased [13].
REFERENCES
Contributed by Gabe Sexton, MD and Svetlana Yatsenko, MD