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

doi:10.1158/2643-3230.BCD-20-0173

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^*

^*Corresponding author for this work

Radiation Oncology

Research output: Contribution to journal › Article › peer-review

45 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.

Original language	English (US)
Pages (from-to)	146-161
Number of pages	16
Journal	Blood cancer discovery
Volume	2
Issue number	2
DOIs	https://doi.org/10.1158/2643-3230.BCD-20-0173
State	Published - Mar 1 2021

Funding

Y. Guan reports a patent for antitumor tet2 modulating compounds pending. A.D. Tiwari reports a patent for antitumor tet2 modulating compounds (WO2019108796A1) pending and owned by Cleveland Clinic. J.G. Phillips reports grants from R35HL135795-01 during the conduct of the study, as well as a patent for PCT/2018/ 063069 issued. D.J. Lindner reports grants from NIH/NCI [P30 CA043703-23 (principal investigator, Gerson)] during the conduct of the study. M. Meggendorfer reports personal fees from MLL Munich Leukemia Laboratory during the conduct of the study. M. Abazeed reports grants from Siemens Medical Solutions, USA, and grants and personal fees from Bayer AG outside the submitted work. M.A. Sekeres reports personal fees from Bristol-Myers Squibb/Celgene and Takeda/Millenium outside the submitted work. J.P. Maciejewski reports grants from NIH during the conduct of the study, as well as patents for TET modulators pending. B.K. Jha reports grants from Cleveland Clinic during the conduct of the study, as well as a patent for antitumor tet2 modulating compounds pending and owned by Cleveland Clinic. No disclosures were reported by the other authors.

ASJC Scopus subject areas

General Medicine

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10.1158/2643-3230.BCD-20-0173

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Guan, Y., Tiwari, A. D., Phillips, J. G., Hasipek, M., Grabowski, D. R., Pagliuca, S., Gopal, P., Kerr, C. M., Adema, V., Radivoyevitch, T., Parker, Y., Lindner, D. J., Meggendorfer, M., Abazeed, M., Sekeres, M. A., Mian, O. Y., Haferlach, T., Maciejewski, J. P., & Jha, B. K. (2021). A Therapeutic Strategy for Preferential Targeting of TET2-Mutant and TET Dioxygenase–Deficient Cells in Myeloid Neoplasms. Blood cancer discovery, 2(2), 146-161. https://doi.org/10.1158/2643-3230.BCD-20-0173

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title = "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.",

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

note = "Funding Information: Y. Guan reports a patent for antitumor tet2 modulating compounds pending. A.D. Tiwari reports a patent for antitumor tet2 modulating compounds (WO2019108796A1) pending and owned by Cleveland Clinic. J.G. Phillips reports grants from R35HL135795-01 during the conduct of the study, as well as a patent for PCT/2018/ 063069 issued. D.J. Lindner reports grants from NIH/NCI [P30 CA043703-23 (principal investigator, Gerson)] during the conduct of the study. M. Meggendorfer reports personal fees from MLL Munich Leukemia Laboratory during the conduct of the study. M. Abazeed reports grants from Siemens Medical Solutions, USA, and grants and personal fees from Bayer AG outside the submitted work. M.A. Sekeres reports personal fees from Bristol-Myers Squibb/Celgene and Takeda/Millenium outside the submitted work. J.P. Maciejewski reports grants from NIH during the conduct of the study, as well as patents for TET modulators pending. B.K. Jha reports grants from Cleveland Clinic during the conduct of the study, as well as a patent for antitumor tet2 modulating compounds pending and owned by Cleveland Clinic. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright}2020 American Association for Cancer Research.",

year = "2021",

month = mar,

day = "1",

doi = "10.1158/2643-3230.BCD-20-0173",

language = "English (US)",

volume = "2",

pages = "146--161",

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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 2021, 'A Therapeutic Strategy for Preferential Targeting of TET2-Mutant and TET Dioxygenase–Deficient Cells in Myeloid Neoplasms', Blood cancer discovery, vol. 2, no. 2, pp. 146-161. https://doi.org/10.1158/2643-3230.BCD-20-0173

TY - JOUR

T1 - A Therapeutic Strategy for Preferential Targeting of TET2-Mutant and TET Dioxygenase–Deficient Cells in Myeloid Neoplasms

AU - Guan, Yihong

AU - Tiwari, Anand D.

AU - Phillips, James G.

AU - Hasipek, Metis

AU - Grabowski, Dale R.

AU - Pagliuca, Simona

AU - Gopal, Priyanka

AU - Kerr, Cassandra M.

AU - Adema, Vera

AU - Radivoyevitch, Tomas

AU - Parker, Yvonne

AU - Lindner, Daniel J.

AU - Meggendorfer, Manja

AU - Abazeed, Mohamed

AU - Sekeres, Mikkeal A.

AU - Mian, Omar Y.

AU - Haferlach, Torsten

AU - Maciejewski, Jaroslaw P.

AU - Jha, Babal K.

N1 - Funding Information: Y. Guan reports a patent for antitumor tet2 modulating compounds pending. A.D. Tiwari reports a patent for antitumor tet2 modulating compounds (WO2019108796A1) pending and owned by Cleveland Clinic. J.G. Phillips reports grants from R35HL135795-01 during the conduct of the study, as well as a patent for PCT/2018/ 063069 issued. D.J. Lindner reports grants from NIH/NCI [P30 CA043703-23 (principal investigator, Gerson)] during the conduct of the study. M. Meggendorfer reports personal fees from MLL Munich Leukemia Laboratory during the conduct of the study. M. Abazeed reports grants from Siemens Medical Solutions, USA, and grants and personal fees from Bayer AG outside the submitted work. M.A. Sekeres reports personal fees from Bristol-Myers Squibb/Celgene and Takeda/Millenium outside the submitted work. J.P. Maciejewski reports grants from NIH during the conduct of the study, as well as patents for TET modulators pending. B.K. Jha reports grants from Cleveland Clinic during the conduct of the study, as well as a patent for antitumor tet2 modulating compounds pending and owned by Cleveland Clinic. No disclosures were reported by the other authors. Publisher Copyright: ©2020 American Association for Cancer Research.

PY - 2021/3/1

Y1 - 2021/3/1

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=85149161216&partnerID=8YFLogxK

U2 - 10.1158/2643-3230.BCD-20-0173

DO - 10.1158/2643-3230.BCD-20-0173

M3 - Article

C2 - 33681816

AN - SCOPUS:85149161216

SN - 2643-3230

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SP - 146

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JO - Blood cancer discovery

JF - Blood cancer discovery

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ER -

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

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