PMID- 34341479
OWN - NLM
STAT- MEDLINE
DCOM- 20220215
LR  - 20220716
IS  - 1476-5551 (Electronic)
IS  - 0887-6924 (Print)
IS  - 0887-6924 (Linking)
VI  - 36
IP  - 2
DP  - 2022 Feb
TI  - Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic 
      leukemia therapy.
PG  - 348-360
LID - 10.1038/s41375-021-01361-8 [doi]
AB  - Despite progress in the treatment of acute lymphoblastic leukemia (ALL), T-cell 
      ALL (T-ALL) has limited treatment options, particularly in the setting of 
      relapsed/refractory disease. Using an unbiased genome-scale CRISPR-Cas9 screen we 
      sought to identify pathway dependencies for T-ALL which could be harnessed for 
      therapy development. Disruption of the one-carbon folate, purine and pyrimidine 
      pathways scored as the top metabolic pathways required for T-ALL proliferation. 
      We used a recently developed inhibitor of SHMT1 and SHMT2, RZ-2994, to 
      characterize the effect of inhibiting these enzymes of the one-carbon folate 
      pathway in T-ALL and found that T-ALL cell lines were differentially sensitive to 
      RZ-2994, with the drug inducing a S/G2 cell cycle arrest. The effects of SHMT1/2 
      inhibition were rescued by formate supplementation. Loss of both SHMT1 and SHMT2 
      was necessary for impaired growth and cell cycle arrest, with suppression of both 
      SHMT1 and SHMT2 inhibiting leukemia progression in vivo. RZ-2994 also decreased 
      leukemia burden in vivo and remained effective in the setting of methotrexate 
      resistance in vitro. This study highlights the significance of the one-carbon 
      folate pathway in T-ALL and supports further development of SHMT inhibitors for 
      treatment of T-ALL and other cancers.
CI  - (c) 2021. The Author(s), under exclusive licence to Springer Nature Limited.
FAU - Pikman, Yana
AU  - Pikman Y
AUID- ORCID: 0000-0002-5336-0216
AD  - Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of 
      Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. 
      yana_pikman@dfci.harvard.edu.
FAU - Ocasio-Martinez, Nicole
AU  - Ocasio-Martinez N
AD  - Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of 
      Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
FAU - Alexe, Gabriela
AU  - Alexe G
AD  - Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of 
      Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
AD  - Broad Institute of Massachusetts Institute of Technology and Harvard University, 
      Cambridge, MA, USA.
AD  - Graduate Program in Bioinformatics, Boston University, Boston, MA, USA.
FAU - Dimitrov, Boris
AU  - Dimitrov B
AD  - Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of 
      Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
FAU - Kitara, Samuel
AU  - Kitara S
AD  - Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of 
      Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
FAU - Diehl, Frances F
AU  - Diehl FF
AD  - Koch Institute for Integrative Cancer Research at Massachusetts Institute of 
      Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
FAU - Robichaud, Amanda L
AU  - Robichaud AL
AD  - Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of 
      Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
FAU - Conway, Amy Saur
AU  - Conway AS
AD  - Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of 
      Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
FAU - Ross, Linda
AU  - Ross L
AD  - Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of 
      Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
FAU - Su, Angela
AU  - Su A
AD  - INSERM UMR 944, IRSL, St Louis Hospital, Paris, France.
FAU - Ling, Frank
AU  - Ling F
AD  - INSERM UMR 944, IRSL, St Louis Hospital, Paris, France.
FAU - Qi, Jun
AU  - Qi J
AUID- ORCID: 0000-0002-1461-3356
AD  - Division of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
FAU - Roti, Giovanni
AU  - Roti G
AD  - Department of Medicine and Surgery, University of Parma, Parma, Italy.
FAU - Lewis, Caroline A
AU  - Lewis CA
AD  - Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
FAU - Puissant, Alexandre
AU  - Puissant A
AD  - INSERM UMR 944, IRSL, St Louis Hospital, Paris, France.
FAU - Vander Heiden, Matthew G
AU  - Vander Heiden MG
AD  - Broad Institute of Massachusetts Institute of Technology and Harvard University, 
      Cambridge, MA, USA.
AD  - Koch Institute for Integrative Cancer Research at Massachusetts Institute of 
      Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
FAU - Stegmaier, Kimberly
AU  - Stegmaier K
AUID- ORCID: 0000-0003-0218-7895
AD  - Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of 
      Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. 
      kimberly_stegmaier@dfci.harvard.edu.
AD  - Broad Institute of Massachusetts Institute of Technology and Harvard University, 
      Cambridge, MA, USA. kimberly_stegmaier@dfci.harvard.edu.
LA  - eng
GR  - P30 CA014051/CA/NCI NIH HHS/United States
GR  - 758848/ERC_/European Research Council/International
GR  - K08 CA222684/CA/NCI NIH HHS/United States
GR  - R35 CA210030/CA/NCI NIH HHS/United States
GR  - F31 CA236036/CA/NCI NIH HHS/United States
GR  - R35 CA242379/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210802
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Enzyme Inhibitors)
RN  - 935E97BOY8 (Folic Acid)
RN  - EC 2.1.2.1 (Glycine Hydroxymethyltransferase)
RN  - EC 2.1.2.1 (SHMT protein, human)
RN  - YL5FZ2Y5U1 (Methotrexate)
SB  - IM
MH  - Animals
MH  - Antimetabolites, Antineoplastic/pharmacology
MH  - Apoptosis
MH  - *CRISPR-Cas Systems
MH  - Cell Cycle
MH  - Cell Proliferation
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - Enzyme Inhibitors/*pharmacology
MH  - Female
MH  - Folic Acid/*metabolism
MH  - Glycine Hydroxymethyltransferase/*antagonists & inhibitors
MH  - Humans
MH  - Methotrexate/*pharmacology
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Mice, SCID
MH  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*drug 
      therapy/enzymology/pathology
MH  - Prognosis
MH  - Tumor Cells, Cultured
MH  - Xenograft Model Antitumor Assays
PMC - PMC8807390
MID - NIHMS1726552
COIS- KS has previously consulted for Novartis, Rigel Pharmaceuticals, AstraZeneca, and 
      Kronos Bio. She consults and has stock options with Auron Therapeutics and 
      received grant funding from Novartis on topics unrelated to this manuscript. MGVH 
      discloses that he is a consultant and advisory board member for Agios 
      Pharmaceuticals, Aeglea Biotherapeutics, iTEOS Therapeutics, Faeth Therapeutics, 
      and Auron Therapeutics.
EDAT- 2021/08/04 06:00
MHDA- 2022/02/16 06:00
PMCR- 2021/08/02
CRDT- 2021/08/03 06:29
PHST- 2020/02/02 00:00 [received]
PHST- 2021/07/20 00:00 [accepted]
PHST- 2021/07/08 00:00 [revised]
PHST- 2021/08/04 06:00 [pubmed]
PHST- 2022/02/16 06:00 [medline]
PHST- 2021/08/03 06:29 [entrez]
PHST- 2021/08/02 00:00 [pmc-release]
AID - 10.1038/s41375-021-01361-8 [pii]
AID - 1361 [pii]
AID - 10.1038/s41375-021-01361-8 [doi]
PST - ppublish
SO  - Leukemia. 2022 Feb;36(2):348-360. doi: 10.1038/s41375-021-01361-8. Epub 2021 Aug 
      2.