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

Yihong Guan, Anand D. Tiwari, James G. Phillips, Metis Hasipek, Dale R. Grabowski, Simona Pagliuca, Priyanka Gopal, Cassandra M. Kerr, Vera Adema, Tomas Radivoyevitch, Yvonne Parker, Daniel J. Lindner, Manja Meggendorfer, Mohamed Abazeed, Mikkeal A. Sekeres, Omar Y. Mian, Torsten Haferlach, Jaroslaw P. Maciejewski, Babal K. Jha

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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 decreases cytosine hydroxymethylation and restricted clonal outgrowth of TET2 mutant but not normal hematopoietic precursor cells in vitro and in vivo. Although TET inhibitor phenocopied somatic TET2 mutations, its pharmacologic effects on normal stem cells are, unlike mutations, reversible. Treatment with TET inhibitor suppresses 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. SIGNIFICANCE: Loss-of-function somatic TET2 mutations are among the most frequent lesions in myeloid neoplasms and associated disorders. Here we report a strategy for selective targeting of residual TET dioxygenase activity in TET-deficient clones that results in restriction of clonal evolution in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)146-161
Number of pages16
JournalCancer discovery
Volume2
Issue number2
DOIs
StatePublished - Mar 1 2021
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

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