E2F1 activation by oncogenic FLT3 internal tandem duplication in regulating purine metabolism in acute myeloid leukaemia

Abstract

Abstract Oncogene FLT3 internal tandem duplication (FLT3-ITD) mutation account for up to 30% of acute myeloid leukaemia (AML) cases and induce transformation.Previously, we found that E2F transcription factor 1 (E2F1) is involved in autophagy in the AML cell line MOLM-13, which harboring the FLT3-ITD. Here, we reported that E2F1 expression was gradually decreased during normal haematopoiesis but was aberrantly upregulated in AML patients carrying FLT3-ITD. E2F1 knockdown in cultured FLT3-ITD-positive AML cells inhibited cell proliferation and increased their cellular sensitivity to all-trans retinoic acid (ATRA) and its derivative 4-amino-2-trifluoromethyl-phenyl resinate (ATPR). Moreover, E2F1-depleted FLT3-ITD+ AML cells lost their malignancy as shown by the reduced leukaemia burden and prolonged survival in leukemic NOD-PrkdcscidIl2rgem1/Smoc mice. Additionally, FLT3-ITD-driven transformation of human CD34+ haematopoietic stem and progenitor cells (HSPCs) was counteracted by E2F1 knockdown. Mechanically, the expression and nuclear accumulation of E2F1 were highly dependent on FLT3-ITD activity. Further study using chromatin immunoprecipitation-sequencing and metabolomics analyses revealed that ectopic FLT3-ITD promoted the recruitment of E2F1 on genes encoding key enzymatic regulators of purine metabolism and thus supported AML cell proliferation. Together, this study demonstrates the dependence of FLT3-ITD+ AML cells on E2F1-regulated purine metabolism, and provides a promising therapeutic strategy for AML patients.