Cooperative epigenetic remodeling by TET2 loss and NRAS mutation drives myeloid transformation and MEK inhibitor sensitivity Journal Article
| Authors: | Kunimoto, H.; Meydan, C.; Nazir, A.; Whitfield, J.; Shank, K.; Rapaport, F.; Maher, R.; Pronier, E.; Meyer, S. C.; Garrett-Bakelman, F. E.; Tallman, M.; Melnick, A.; Levine, R. L.; Shih, A. H. |
| Article Title: | Cooperative epigenetic remodeling by TET2 loss and NRAS mutation drives myeloid transformation and MEK inhibitor sensitivity |
| Abstract: | Mutations in epigenetic modifiers and signaling factors often co-occur in myeloid malignancies, including TET2 and NRAS mutations. Concurrent Tet2 loss and NrasG12D expression in hematopoietic cells induced myeloid transformation, with a fully penetrant, lethal chronic myelomonocytic leukemia (CMML), which was serially transplantable. Tet2 loss and Nras mutation cooperatively led to decrease in negative regulators of mitogen-activated protein kinase (MAPK) activation, including Spry2, thereby causing synergistic activation of MAPK signaling by epigenetic silencing. Tet2/Nras double-mutant leukemia showed preferential sensitivity to MAPK kinase (MEK) inhibition in both mouse model and patient samples. These data provide insights into how epigenetic and signaling mutations cooperate in myeloid transformation and provide a rationale for mechanism-based therapy in CMML patients with these high-risk genetic lesions. Kunimoto et al. show that concurrent Tet2 loss and NrasG12D expression in hematopoietic cells induces fully penetrant, lethal chronic myelomonocytic leukemia by decreasing negative regulators of MAPK activation. Mouse and human TET2/NRAS double-mutant leukemia show preferential sensitivity to MEK inhibition. © 2017 Elsevier Inc. |
| Keywords: | adult; child; controlled study; preschool child; young adult; chronic myelomonocytic leukemia; gene mutation; human cell; nonhuman; animal cell; mouse; animal tissue; animal experiment; animal model; enzyme activation; oncogene; epigenetics; hematopoietic cell; gene loss; gene silencing; malignant transformation; tet2 gene; n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide; oncogene n ras; selumetinib; mitogen activated protein kinase kinase inhibitor; cancer epigenetics; mapk signaling; human; male; female; priority journal; article; binimetinib; targeted therapeutics; thp-1 cell line; leukemia biology; molm-13 cell line |
| Journal Title: | Cancer Cell |
| Volume: | 33 |
| Issue: | 1 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2018-01-08 |
| Start Page: | 44 |
| End Page: | 59.e8 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2017.11.012 |
| PUBMED: | 29275866 |
| PROVIDER: | scopus |
| PMCID: | PMC5760367 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 December 2018 -- Source: Scopus |
