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

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

  • Blood Cancer Discov. 2021 Mar;2(2):146-161. doi: 10.1158/2643-3230.BCD-20-0173.
Yihong Guan 1,  Anand D Tiwari 1,  James G Phillips 1,  Metis Hasipek 1,  Dale R Grabowski 1,  Simona Pagliuca 1,  Priyanka Gopal 1,  Cassandra M Kerr 1,  Vera Adema 1,  Tomas Radivoyevitch 2,  Yvonne Parker 1,  Daniel J Lindner 1,  Manja Meggendorfer 3,  Mohamed Abazeed 1 4 5,  Mikkeal A Sekeres 1 4 5 6,  Omar Y Mian 1 4 6,  Torsten Haferlach 3,  Jaroslaw P Maciejewski 7 4 5 6,  Babal K Jha 7 4 6
Affiliations

Affiliations

  • 1 Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, Ohio.
  • 2 Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio.
  • 3 Munich Leukemia Laboratory, Munich, Germany.
  • 4 Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio.
  • 5 Leukemia Program, Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, Ohio.
  • 6 Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
  • 7 Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, Ohio. jhab@ccf.org maciejj@ccf.org.
PMID: 33681816 DOI: 10.1158/2643-3230.BCD-20-0173
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.

Keywords

2-hydroxygluterate; 5hmC; IDH; MDS; TET2; α-ketoglutarate.

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