Abstract
Overlapping spectrum of mutated genes affected in myelodysplastic syndrome (MDS) and primary acute myeloid leukemia suggest common pathogenic mechanisms. However, the frequencies of specific mutations are significantly different between them, which implies they might determine specific disease phenotype. For instance, there are overrepresentations of mutations in RNA splicing factors or epigenetic regulators in MDS. We provide an overview of recent advances in our understanding of the biology of MDS and related disorders. Our focus is how mutations of in splicing factors or epigenetic regulators identified in MDS patients demonstrate phenotypes in knockin/knockout mouse models. For instance, mutant Srsf2 mice could alter Srsf2’s normal sequence-specific RNA binding activity. It exhibited changing in the recognition of specific exonic splicing enhancer motifs to drive recurrent missplicing of Ezh2, which reduces Ezh2 expression by promoting nonsense-mediated decay. Consistent with this, SRSF2 mutations are mutually exclusive with EZH2 loss-of-function mutations in MDS patients. We also review how gene editing technology identified unique associations between pathogenic mechanisms and targeted therapy using lenalidomide, including: (i) how haploinsufficiency of the genes located in the commonly deleted region in del(5q) MDS patients promotes MDS; (ii) how lenalidomide causes selective elimination of del(5q) MDS cells; and (iii) why del(5q) MDS patients become resistant to lenalidomide. Thus, this review describes our current understanding of the mechanistic and biological effects of mutations in spliceosome and epigenetic regulators by comparing wild-type normal to mutant function as well as a brief overview of the recent progresses in MDS biology.
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Acknowledgements
This work was supported by US National Institute of Health (NIH) grants R35 HL135795, R01HL123904, R01 HL118281, R01 HL128425, R01 HL132071, a grant from Edward P. Evans Foundation (Maciejewski) and a grant JSPS Overseas Research Fellow (Nagata).
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Nagata, Y., Maciejewski, J.P. The functional mechanisms of mutations in myelodysplastic syndrome. Leukemia 33, 2779–2794 (2019). https://doi.org/10.1038/s41375-019-0617-3
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