Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood cancer discovery	2	2	2021 Mar	146-161	Blood Cancer Discov

URL

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
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
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