FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia Journal Article
| Authors: | Sung, P. J.; Selvam, M.; Riedel, S. S.; Xie, H. M.; Bryant, K.; Manning, B.; Wertheim, G. B.; Kulej, K.; Pham, L.; Bowman, R. L.; Peresie, J.; Nemeth, M. J.; Levine, R. L.; Garcia, B. A.; Meyer, S. E.; Sidoli, S.; Bernt, K. M.; Carroll, M. |
| Article Title: | FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia |
| Abstract: | Internal tandem duplication mutations in fms-like tyrosine kinase 3 (FLT3-ITD) are recurrent in acute myeloid leukemia (AML) and increase the risk of relapse. Clinical responses to FLT3 inhibitors (FLT3i) include myeloid differentiation of the FLT3-ITD clone in nearly half of patients through an unknown mechanism. We identified enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), as a mediator of this effect using a proteomic-based screen. FLT3i downregulated EZH2 protein expression and PRC2 activity on H3K27me3. FLT3-ITD and loss-of-function mutations in EZH2 are mutually exclusive in human AML. We demonstrated that FLT3i increase myeloid maturation with reduced stem/progenitor cell populations in murine Flt3-ITD AML. Combining EZH1/2 inhibitors with FLT3i increased terminal maturation of leukemic cells and reduced leukemic burden. Our data suggest that reduced EZH2 activity following FLT3 inhibition promotes myeloid differentiation of FLT3-ITD leukemic cells, providing a mechanistic explanation for the clinical observations. These results demonstrate that in addition to its known cell survival and proliferation signaling, FLT3-ITD has a second, previously undefined function to maintain a myeloid stem/progenitor cell state through modulation of PRC2 activity. Our findings support exploring EZH1/2 inhibitors as therapy for FLT3-ITD AML. © The Author(s), under exclusive licence to Springer Nature Limited 2024. |
| Keywords: | signal transduction; controlled study; protein expression; unclassified drug; gene mutation; genetics; mutation; leukemia, myeloid, acute; nonhuman; animal cell; mouse; animal; metabolism; animals; mice; gene; cell survival; enzyme inhibition; cell maturation; protein kinase inhibitor; cell differentiation; cell population; protein tyrosine kinase; proteomics; stem cell; protein kinase inhibitors; histone h3; leukemia cell; down regulation; protein-tyrosine kinases; bone marrow cell; loss of function mutation; protein inhibitor; transcription factor ezh2; cd135 antigen; acute myeloid leukemia; fms-like tyrosine kinase 3; polycomb repressive complex 2; internal tandem duplication mutation; disease burden; humans; human; article; gsk 126; flt3 protein, human; flt3 itd gene |
| Journal Title: | Leukemia |
| Volume: | 38 |
| Issue: | 2 |
| ISSN: | 0887-6924 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-01-01 |
| Start Page: | 291 |
| End Page: | 301 |
| Language: | English |
| DOI: | 10.1038/s41375-023-02131-4 |
| PUBMED: | 38182819 |
| PROVIDER: | scopus |
| PMCID: | PMC11141246 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
