Contributed by Pooja Srivastava MD, Svetlana A. Yatsenko, MD, DABMGG, FACMGDISCUSSION
KMT2A is a 430 kD transcription factor and resembles the drosophila trithorax (TRX) gene. Its structure includes three AT-hook domains for DNA binding, a methyltransferase homology domain, and a SET domain (7). Several authors have described that KMT2A fusion proteins can be either formed by KMT2A fusion with a partner gene with intrinsic transcriptional activity which mediates leukemogenesis or to partners which result in dimerization of the KMT2A fragment serving as a pro-leukemogenic factor(7-9). KMT2A-PTD is suggested to resemble the dimerized KMT2A type of translocations(8). These duplications consist of an in-frame repetition of a segment containing exons 2-6, 2-7, 2-8, or exons 3-9, 3-10, 3-11, leading to a potentially translatable sequence (1, 5, 10). When compared to KMT2A chimeric fusion proteins which arise from translocations, the KMT2A-PTD protein retains the C-terminal domains and the histone H3 lysine 4 methyltransferase activity (6, 7).
As seen in our case, the KMT2A-PTD cannot be detected by conventional cytogenetic studies but can be diagnosed by whole genome microarray. The finding of a cryptic KMT2A alteration in patients with normal karyotype has provided a molecular basis for diagnosis as well as guiding treatment. In the presence of KMT2A-PTD, a wild type KMT2A is epigenetically silenced. Combination of a DNA methyltransferase and/or histone deacetylase inhibitors can induce re-expression of KMT2A, sensitizing myeloid blasts to standard chemotherapy regimens and activating apoptotic mechanisms (5, 11-13).
KMT2A-PTD genomic alteration is not exclusively associated with AML, but also has been observed in childhood and adult ALL, and myelodysplastic syndrome. The KMT2A gene is essential for differentiation of myeloid and macrophage hematopoietic cells(14). Since the KMT2A-PTD has been seen in various subtypes of AML, probably the PTD affects the precursor cells before lineage commitment, or is capable of affecting cells across different lineages of myeloid differentiation (8).
KMT2A-PTD is believed to act as an oncogenic driver by modulating the expression of HOX genes(1). However, its exact mechanism of action is not clear. Multiple mutations occur along with KMT2A-PTD and they are usually acquired in a sequential manner: IDH2/DNMT3A/U2AF1/TET2 ->KMT2A-PTD ->RAS-RTK. This hypothesis was based on the fact that in patients in remission, KMT2A-PTD was absent while mutations of IDH2, DNMT3A, TET2 and U2AF1 were retained, suggesting that these mutations were acquired before KMT2A-PTD(1). In our case, DNMT3A and IDH1 mutations were also detected, and likely represent the early driver mutations. After acquiring initiating mutations, a premalignant clone is generated which later gains other mutations ultimately leading to leukemogenesis. Thus, KMT2A-PTD has been proposed to occur as a secondary cooperating mutation(1) although additional studies are necessary to corroborate this hypothesis.
KMT2A-PTD has been suggested to confer a poor prognosis and shorter disease-free survival (2, 8, 14, 15). Monitoring of the KMT2A-PTD transcript levels can be used as a potential marker for the early prediction of cytomorphological relapse as the molecular relapse (increase of at least 1-log) was found to precede the cytomorphological relapse by approximately 35 days(7). As this chromosomal aberration is well recognized and has prognostic implications, it is important to test for KMT2A-PTD in all cases of AML, and especially in those with normal cytogenetic studies. Qualitative and quantitative assessment of KMT2A-PTD both for initial diagnosis and follow up management can be really helpful in treatment planning and monitoring of the disease.
REFERENCES
Contributed by Pooja Srivastava MD, Svetlana A. Yatsenko, MD, DABMGG, FACMG
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