CARM1 is essential for myeloid leukemogenesis but dispensable for normal hematopoiesis Journal Article
| Authors: | Greenblatt, S. M.; Man, N.; Hamard, P. J.; Asai, T.; Karl, D.; Martinez, C.; Bilbao, D.; Stathais, V.; McGrew-Jermacowicz, A.; Duffort, S.; Tadi, M.; Blumenthal, E.; Newman, S.; Vu, L.; Xu, Y.; Liu, F.; Schurer, S. C.; McCabe, M. T.; Kruger, R. G.; Xu, M.; Yang, F. C.; Tenen, D.; Watts, J.; Vega, F.; Nimer, S. D. |
| Article Title: | CARM1 is essential for myeloid leukemogenesis but dispensable for normal hematopoiesis |
| Abstract: | Chromatin-modifying enzymes, and specifically the protein arginine methyltransferases (PRMTs), have emerged as important targets in cancer. Here, we investigated the role of CARM1 in normal and malignant hematopoiesis. Using conditional knockout mice, we show that loss of CARM1 has little effect on normal hematopoiesis. Strikingly, knockout of Carm1 abrogates both the initiation and maintenance of acute myeloid leukemia (AML) driven by oncogenic transcription factors. We show that CARM1 knockdown impairs cell-cycle progression, promotes myeloid differentiation, and ultimately induces apoptosis. Finally, we utilize a selective, small-molecule inhibitor of CARM1 to validate the efficacy of CARM1 inhibition in leukemia cells in vitro and in vivo. Collectively, this work suggests that targeting CARM1 may be an effective therapeutic strategy for AML. Greenblatt et al. show that loss of the protein arginine methyltransfersase CARM1 minimally impacts normal hematopoiesis but strongly impairs leukemogenesis by regulating cell-cycle progression, myeloid differentiation, and apoptosis. Targeting CARM1 reduces AML growth in primary patient samples and mouse models. © 2018 Elsevier Inc. |
| Keywords: | controlled study; human tissue; protein expression; unclassified drug; nonhuman; animal cell; mouse; animal tissue; cell viability; enzyme inhibition; protein depletion; protein targeting; animal experiment; animal model; transcription factor; in vivo study; cell differentiation; in vitro study; enzyme activity; transcription regulation; epigenetics; leukemia cell; leukemogenesis; hematopoiesis; spleen weight; helper cell; chromatin assembly and disassembly; protein arginine methyltransferase; aml; spleen size; aml1-eto; acute myeloid leukemia; cell self-renewal; antileukemic agent; arginine methyltransferase; methyltransferase inhibitor; mll-af9; human; priority journal; article; carm1; ic50; coactivator associated arginine methyltransferase 1; epz 025654; epz 029751; ezm 2302; skno-1 cell line |
| Journal Title: | Cancer Cell |
| Volume: | 33 |
| Issue: | 6 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2018-06-11 |
| Start Page: | 1111 |
| End Page: | 1127.e5 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2018.05.007 |
| PROVIDER: | scopus |
| PUBMED: | 29894694 |
| PMCID: | PMC6191185 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 July 2018 -- Source: Scopus |
