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A Therapeutic Strategy for Preferential Targeting of TET2 Mutant and TET-dioxygenase Deficient Cells in Myeloid Neoplasms.

ABSTRACT: 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.

SUBMITTER: Guan Y

PROVIDER: S-EPMC7935131 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

A Therapeutic Strategy for Preferential Targeting of TET2 Mutant and TET-dioxygenase Deficient Cells in Myeloid Neoplasms.

Guan Yihong Y Tiwari Anand D AD Phillips James G JG Hasipek Metis M Grabowski Dale R DR Pagliuca Simona S Gopal Priyanka P Kerr Cassandra M CM Adema Vera V Radivoyevitch Tomas T Parker Yvonne Y Lindner Daniel J DJ Meggendorfer Manja M Abazeed Mohamed M Sekeres Mikkeal A MA Mian Omar Y OY Haferlach Torsten T Maciejewski Jaroslaw P JP Jha Babal K BK

Blood cancer discovery 20201207 2

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 inh ...[more]

PMID: 33681816

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Project description:Acute myelogenous leukemia (AML) is a heterogeneous disease characterized by myeloid progenitor cells uncontrolled proliferation gradually replacing normal hematopoiesis. To evaluate Ten Eleven Translocation 2 gene (TET2) single nucleotide polymorphism (SNP) (rs2454206, rs34402524, rs61744960) in AML, and chronic myeloid leukemia (CML) in relation to their disease prognostic criteria. The study included 136 subjects; 52 AML, 54 CML and 30 subjects as control group matched for age and sex. Routine investigations including CBC, bone marrow aspiration, flow cytometry biochemical investigations and cytogenetics and molecular study were performed accordingly. DNA extraction and SNP assay for TET2 gene polymorphism was done using (Thermo-Fisher predesigned SNP, USA) PCR prism 7500. The mean age was 43.4 ± 14.0 years in AML patients, 45.98 ± 15.7 years in CML patients and 39.3 ± 6.587 years in control group (p > 0.05). The frequency of TET2 SNP rs 34402524 ranged from heterozygous to homozygous in both AML (46%, 54%) and CML (48%, 46.2%) groups but was mainly homozygous among the control (80%) group (p = 0.012). TET2 SNP rs 2454206 was mainly wild in CML (65.4%) and control (63.3%) groups compared to AML as wild was only in (46%) and heterozygous in (44%) with only 10% being homozygous (p = 0.046). TET2 SNP rs 61744960 showed a homozygous pattern among all three group (AML CML and control) showing no statistical significance (p = 0.528). Eventhough, higher non responders to treatment were among homozygous and heterozygous groups yet, response to therapy as respect to specific TET2 SNP showed no significant variation (p > 0.05). TET2 SNP in CML cases did not alter the prognostic criteria as no statistical significance was noted (p > 0.05) except for TET2 SNP rs 34402524 where homozygous cases had larger spleen size (p = 0.019). TET2 SNP is common in Egyptian myeloid neoplasm. This is the first study in this field and further studies are recommended to investigate TET2 and relation to other hematological malignancies and leukemogenesis transformation.

Dataset Information

A Therapeutic Strategy for Preferential Targeting of TET2 Mutant and TET-dioxygenase Deficient Cells in Myeloid Neoplasms.

Publications

A Therapeutic Strategy for Preferential Targeting of TET2 Mutant and TET-dioxygenase Deficient Cells in Myeloid Neoplasms.

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