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Ref Type Journal Article
PMID (33681816)
Authors Guan Y, Tiwari AD, Phillips JG, Hasipek M, Grabowski DR, Pagliuca S, Gopal P, Kerr CM, Adema V, Radivoyevitch T, Parker Y, Lindner DJ, Meggendorfer M, Abazeed M, Sekeres MA, Mian OY, Haferlach T, Maciejewski JP, Jha BK
Title A Therapeutic Strategy for Preferential Targeting of TET2 Mutant and TET-dioxygenase Deficient Cells in Myeloid Neoplasms.
Abstract Text TET2 is frequently mutated in myeloid neoplasms. Genetic TET2 deficiency leads to skewed myeloid differentiation and clonal expansion, but minimal residual TET activity is critical for survival of neoplastic progenitor and stem cells. Consistent with mutual exclusivity of TET2 and neomorphic IDH1/2 mutations, here we report that IDH1/2 mutant-derived 2-hydroxyglutarate is synthetically lethal to TET-dioxygenase deficient cells. In addition, a TET-selective small molecule inhibitor decreased cytosine hydroxymethylation and restricted clonal outgrowth of TET2 mutant, but not normal hematopoietic precursor cells in vitro and in vivo. While TET-inhibitor phenocopied somatic TET2 mutations, its pharmacologic effects on normal stem cells were, unlike mutations, reversible. Treatment with TET inhibitor suppressed the clonal evolution of TET2 mutant cells in murine models and TET2-mutated human leukemia xenografts. These results suggest that TET inhibitors may constitute a new class of targeted agents in TET2 mutant neoplasia.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
TETi76 TETi76 3 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
TETi76 TETi76, is an inhibitor of TET-dioxygeases, potentially resulting in decreased tumor cell proliferation and reduced tumor growth (PMID: 33681816).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
IDH1 R132C leukemia sensitive TETi76 Preclinical - Cell culture Actionable In a preclinical study, TETi76 treatment decreased viability of a leukemia cell line expressing IDH1 R132C in culture (PMID: 33681816). 33681816
IDH2 R140Q leukemia sensitive TETi76 Preclinical - Cell culture Actionable In a preclinical study, TETi76 treatment decreased viability of a leukemia cell line expressing IDH2 R140Q in culture (PMID: 33681816). 33681816
TET2 loss leukemia sensitive TETi76 Preclinical - Cell line xenograft Actionable In a preclinical study, TETi76 treatment reduced viability and colony formation of a TET2-null leukemia cell line in culture, decreased viability of bone marrow derived mononuclear cells from TET2-null mouse model, and reduced tumor burden in a TET2-null subcutaneous xenograft model (PMID: 33681816). 33681816