Targeting MTHFD2 in acute myeloid leukemia.
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.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215.
Yana
Y
Pikman
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215 Institut National de la Santé et de la Recherche Medicale U1065, Team 2, C3M, 06204 Nice, France.
Alexandre
A
Puissant
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215 Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142 Bioinformatics Graduate Program, Boston University, Boston, MA 02215.
Gabriela
G
Alexe
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215.
Andrew
A
Furman
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215.
Liying M
LM
Chen
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215.
Stacey M
SM
Frumm
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215.
Linda
L
Ross
Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Massachusetts Institute of Technology, Cambridge, MA 02142.
Nina
N
Fenouille
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215.
Christopher F
CF
Bassil
Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Massachusetts Institute of Technology, Cambridge, MA 02142.
Caroline A
CA
Lewis
Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Massachusetts Institute of Technology, Cambridge, MA 02142.
Azucena
A
Ramos
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142.
Joshua
J
Gould
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.
Richard M
RM
Stone
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.
Daniel J
DJ
DeAngelo
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.
Ilene
I
Galinsky
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142.
Clary B
CB
Clish
Department of Pediatrics, Columbia University Medical Center, New York, NY 10032.
Andrew L
AL
Kung
Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Massachusetts Institute of Technology, Cambridge, MA 02142.
Michael T
MT
Hemann
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142 Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Massachusetts Institute of Technology, Cambridge, MA 02142.
Matthew G
MG
Vander Heiden
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215 Research Institute of Oncology and Hematology at CancerCare Manitoba and the University of Manitoba, Winnipeg R3E OV9, Manitoba, Canada.
Versha
V
Banerji
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215 Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142 kimberly_stegmaier@dfci.harvard.edu.
Kimberly
K
Stegmaier
D000818:Animals; D002952:Citric Acid Cycle; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D018922:HL-60 Cells; D064593:Heterografts; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000453:epidemiology* / Q000235:genetics / Q000628:therapy; D045064:Methenyltetrahydrofolate Cyclohydrolase / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009368:Neoplasm Transplantation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D020298:U937 Cells
C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D045064:Methenyltetrahydrofolate Cyclohydrolase