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 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. See related video: https://aacrjournals.org/webinar-minimal-tet-activity-targetable-vulnerability-tet2-and-neomorphic-idh12-mutant

TET2 mutations as a part of DNA dioxygenase deficiency in myelodysplastic syndromes

“…In particular, we previously demonstrated that TET2 deletion caused proliferative advantage of K562 over control cells and further deletion of either TET1 or TET3 led to a significant reduction of global 5-hmC parallel to a severe cellular growth impairment. 3 The high frequency of TET2 mutations in myeloid neoplasia (MN) and the sole function of TET-dioxygenases as 5-hmC hydroxylases emphasize the crucial role of this gene in controlling the fate of HSPCs by epigenetic regulation of lineagecommitment and self-renewal programs, including differentiation and skewing of monocytic lineage. 8,9 Indeed, our group has recently published on the beneficial effect of a TET-selective small molecule inhibitor blocking the clonal outgrowth of TET2 mutant cells.…”

“…8,9 Indeed, our group has recently published on the beneficial effect of a TET-selective small molecule inhibitor blocking the clonal outgrowth of TET2 mutant cells. 3 TET2 mutations are also frequent in clonal hematopoiesis of indeterminate potential (CHIP) and may represent an adaptive response of the immune system to age-related attrition of HSPC compartment. 13,14 The clinical course of CHIP TETopathy in myelodysplastic syndromes Gurnari et al, 2021 4 carriers suggests that TET2 hits are weak drivers; a conclusion also supported by the lack of impact of TET2 mutations on survival and progression-free survival in MDS.…”

TP53 in Myelodysplastic Syndromes

“…The survival and proliferation of cells with TET2 mutations are critically dependent on residual TET activity derived mostly from TET3 and TET1. The TET inhibitor transiently suppresses the residual methylcytosine dioxygenase activity and eventually eliminates the tumor initiating clones with TET2 mutations [ 63 ]. This result suggests that the combination of specific TET and TP53 target drugs could be considered as a new therapeutic strategy for MDS patients presenting these two concurrent mutant genes.…”

The Interactome between Metabolism and Gene Mutations in Myeloid Malignancies

“…Besides HMA, our group has recently developed a new therapeutic approach which entails the use of a TET-selective small-molecule inhibitor able to selectively suppress TET2-mutant cells in mouse models and TET2-mutated human leukemia xenografts while sparing normal cells [53].…”