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|Ref Type||Journal Article|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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|