Myeloid translocation gene CBFA2T3 directs a relapse gene program and determines patient-specific outcomes in AML
2019
CBFA2T3 is a master
transcriptional coregulatorin hematopoiesis. In this study, we report novel functions of CBFA2T3 in acute myeloid leukemia (AML) relapse. CBFA2T3 regulates cell-fate genes to establish gene expression signatures associated with leukemia stem cell (LSC) transformation and relapse. Gene set enrichment analysis showed that CBFA2T3 expression marks LSC signatures in primary AML samples. Analysis of paired primary and relapsed samples showed that acquisition of LSC
gene signaturesinvolves cell type–specific activation of CBFA2T3 transcription via the NM_005187 promoter by GCN5. Short hairpin RNA – mediated downregulation of CBFA2T3 arrests G1/
S cellcycle progression, diminishes LSC
gene signatures, and attenuates in vitro and in vivo proliferation of AML cells. We also found that the
RUNX1-
RUNX1T1fusion protein transcriptionally represses NM_005187 to confer t(8;21) AML patients a natural resistance to relapse, whereas lacking a similar repression mechanism renders non–
core-binding factorAML patients highly susceptible to relapse. These studies show that 2 related primary AML-associated factors, the expression level of CBFA2T3 and the ability of leukemia cells to repress cell type–specific CBFA2T3 gene transcription, play important roles in patient prognosis, providing a paradigm that differential abilities to repress hematopoietic coregulator gene transcription are correlated with patient-specific outcomes in AML.
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