Case 1080 - Germline GATA2 Mutation in Myelodysplasia-related Acute Myeloid Leukemia

Contributed by Gabe Sexton, MD and Svetlana Yatsenko, MD


Myelodysplastic syndrome (MDS) is a clonal disorder of bone marrow stem cells characterized by ineffective hematopoiesis and cytopenias. MDS most commonly arises in older individuals, with a median age at diagnosis of 65-70 years and an annual incidence of 3.1 per 100,000 [1, 2]. Progression to acute myeloid leukemia (AML) is a dangerous complication of MDS, occurring in about one third of cases [1, 3]. Cytogenetic abnormalities are important diagnostic and prognostic factors in MDS, and are more likely to involve unbalanced chromosomal changes in MDS than in AML [4]. Frequently observed abnormalities include 5q deletion, monosomy 7, and trisomy 8 [4]. Pediatric MDS is considerably less common than MDS in adults, with an estimated annual incidence of 1.8 cases per 1 million children aged 0-14 years [5]. Allogeneic hematopoietic stem cell transplant (HSCT) is the primary treatment for both MDS and AML in children [5].


An adolescent girl with a past medical history of prematurity, asthma, eczema, and environmental allergies presented to her primary care clinic for evaluation of neck pain. Neck X-ray and CT images obtained at her local ED showed no acute abnormalities. On follow-up with her pediatrician, a CBC showed macrocytic anemia with Hgb of 9.8, Hct of 31.3, MCV of 107.2, and RDW of 17.1%. Her WBC and platelet count were within normal limits.

Examination of a subsequent bone marrow biopsy showed a myeloid neoplasm with approximately 10% blasts. Sheets of megakaryocytes exhibiting dyspoiesis were also observed. Flow cytometric analysis of bone marrow demonstrated a myeloid blast population of about 17%. Fluorescence in situ hybridization (FISH) analysis was negative for RUNX1T1/RUNX1, BCR/ABL1, NUP98, KMT2A, and MYH11/CBFB gene rearrangements. Karyotype analysis showed two abnormal related clones: the stemline with monosomy 7 and a sideline with monosomy 7 and trisomy 8 (Figure 1A, B). The patient was diagnosed with MDS based on these results. Workup of the patient's neck pain showed brachial plexitis on MR imaging, concerning for extra-medullary disease. The patient was scheduled for a repeat bone marrow biopsy, which demonstrated 25% blasts. Following the repeat biopsy, the diagnosis was changed to myelodysplasia-related AML. Further workup included bone marrow mutational analysis, which was negative for internal tandem duplication of the FLT3 gene as well as the FLT3 D835 mutation. Next-generation sequencing of the patient's bone marrow identified mutations in the following genes: ETV6 (c.827del; allele fraction [AF]: 66%), EZH2 (c.82_85dup; AF: 33%), ASXL1 (c.1933_1934del; AF: 17%), and SETBP1 (c.2608G>A; AF: 6%). Whole genome CGH+SNP microarray demonstrated a loss of chromosome 7, confirmed by FISH (Figure 1C), and showed a gain of chromosome 8 in a subset of the cells (Figure 1E). Microarray analysis also revealed a cryptic deletion in the 3q21 region containing the GATA2 gene (Figure 1F). Further FISH studies were negative for MECOM gene rearrangement, ruling out inv(3)(q21q26) that is common in AML.

Following diagnosis of AML, chemotherapy was initiated with CPX-351. A bone marrow biopsy performed upon completion of induction chemotherapy showed hypocellular marrow with no morphologic or immunophenotypic evidence of AML. A follow-up biopsy showed no increase in blasts, and the patient was scheduled for allogeneic umbilical cord blood transplant from an HLA-mismatched unrelated donor.

     Figure 1. Aberrations detected by G-banding, FISH, and array-CGH analysis.

A) A stemline karyotype showing a clone with monosomy 7 (red arrow). B) A subclone with monosomy 7 and trisomy 8 (blue arrow). C) Interphase FISH analysis using probes specific for chromosome 7 centromere (D7Z1, green signal) and 7q31 (D7S486, red signal) demonstrated a population of cells with one red and one green signal indicative of monosomy 7. D) Interphase FISH analysis negative for the MECOM (located at 3q26) break-a-part gene rearrangement. E) Whole genome array CGH plot. Microarray probes are arranged according to their physical map locations on each chromosome from the distal p-arm (on the left) to the distal q-arm (on the right). Chromosomes are plotted in a horizontal fashion and are listed at the bottom. An average logarithmic ratio (log2) is displayed as a black line for all oligonucleotide probes. Probes with a log2 average clustered around zero indicate DNA segments with normal copy numbers. A positive log2 ratio (above zero) indicates a gain (extra copy) of the chromosomal region, while intervals with a negative log2 ratio (below zero) represent loss of DNA copy number. Array-CGH analysis demonstrated a loss of all probes specific for chromosome 7 (red shaded area) with log2= - 0.6 and a gain of chromosome 8-specific probes (blue shaded area) with log2=+0.2, consistent with monosomy 7 and trisomy 8 in ~60% and 20% of cells, respectively. A cryptic loss in the 3q21.3 region is indicated by a red arrow. F) A magnified view of the array-CGH plot for the 3q21.3 region. Each dot represents an oligonucleotide probe. The black dots indicate probes without change in copy number and red dots indicate a single copy loss. Abnormal region including the GATA2 gene is highlighted in red (deletion). The log2 ratio of -1 is suggestive of a constitution abnormality (deletion present in all of the cells).


Case IndexCME Case StudiesFeedbackHome