Targeting MTHFD2 in acute myeloid leukemia
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Author
Pikman, Yana
Puissant, Alexandre
Alexe, Gabriela
Furman, Andrew
Chen, Liying M.
Frumm, Stacey M.
Ross, Linda
Fenouille, Nina
Bassil, Christopher F.
Lewis, Caroline A.
Ramos, Azucena
Gould, Joshua
Stone, Richard M.
DeAngelo, Daniel J.
Galinsky, Ilene
Clish, Clary B.
Kung, Andrew L.
Hemann, Michael T.
Banerji, Versha
Stegmaier, Kimberly
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1084/jem.20151574Metadata
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Pikman, Y., A. Puissant, G. Alexe, A. Furman, L. M. Chen, S. M. Frumm, L. Ross, et al. 2016. “Targeting MTHFD2 in acute myeloid leukemia.” The Journal of Experimental Medicine 213 (7): 1285-1306. doi:10.1084/jem.20151574. http://dx.doi.org/10.1084/jem.20151574.Abstract
Drugs targeting metabolism have formed the backbone of therapy for some cancers. We sought to identify new such targets in acute myeloid leukemia (AML). The one-carbon folate pathway, specifically methylenetetrahydrofolate dehydrogenase-cyclohydrolase 2 (MTHFD2), emerged as a top candidate in our analyses. MTHFD2 is the most differentially expressed metabolic enzyme in cancer versus normal cells. Knockdown of MTHFD2 in AML cells decreased growth, induced differentiation, and impaired colony formation in primary AML blasts. In human xenograft and MLL-AF9 mouse leukemia models, MTHFD2 suppression decreased leukemia burden and prolonged survival. Based upon primary patient AML data and functional genomic screening, we determined that FLT3-ITD is a biomarker of response to MTHFD2 suppression. Mechanistically, MYC regulates the expression of MTHFD2, and MTHFD2 knockdown suppresses the TCA cycle. This study supports the therapeutic targeting of MTHFD2 in AML.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925018/pdf/Terms of Use
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