Targeting MTH FD2 in acute myeloid leukemia

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 (MTH FD2), emerged as a top candidate in our analyses. MTH FD2 is the most differentially expressed metabolic enzyme in cancer versus normal cells. Knockdown of MTH FD2 in AML cells decreased growth, induced differentiation, and impaired colony formation in primary AML blasts. In human xenograft and MLL-AF9 mouse leukemia models, MTH FD2 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 MTH FD2 suppression. Mechanistically, MYC regulates the expression of MTH FD2, and MTH FD2 knockdown suppresses the TCA cycle. This study supports the therapeutic targeting of MTH FD2 in AML.