Consecutive epigenetically-active agent combinations act in ID1-RUNX3-TET2 and HOXA pathways for Flt3ITD+ve AML

Hamid Sayar, Yan Liu, Rui Gao, Mohammad Abu Zaid, Larry Cripe, Jill Weisenbach, Katie J. Sargent, Mehdi Nassiri, Lang Li, Heiko Konig, Attaya Suvannasankha, Feng Pan, Rajasubramaniam Shanmugam, Chirayu Goswami, Reuben Kapur, Mingjiang Xu, H. Scott Boswell

Research output: Contribution to journalArticle

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Abstract

Co-occurrence of Flt3ITD and TET2 mutations provoke an animal model of AML by epigenetic repression of Wnt pathway antagonists, including RUNX3, and by hyperexpression of ID1, encoding Wnt agonist. These affect HOXA over-expression and treatment resistance. A comparable epigenetic phenotype was identified among adult AML patients needing novel intervention. We chose combinations of targeted agents acting on distinct effectors, at the levels of both signal transduction and chromatin remodeling, in relapsed/refractory AML's, including Flt3ITD+ve, described with a signature of repressed tumor suppressor genes, involving Wnt antagonist RUNX3, occurring along with ID1 and HOXA over-expressions. We tracked patient response to combination of Flt3/Raf inhibitor, Sorafenib, and Vorinostat, pan-histone deacetylase inhibitor, without or with added Bortezomib, in consecutive phase I trials. A striking association of rapid objective remissions (near-complete, complete responses) was noted to accompany induced early pharmacodynamic changes within patient blasts in situ, involving these effectors, significantly linking RUNX3/Wnt antagonist de-repression (80%) and ID1 downregulation (85%), to a response, also preceded by profound HOXA9 repression. Response occurred in context of concurrent TET2 mutation/hypomorphy and Flt3ITD+ve mutation (83% of complete responses). Addition of Bortezomib to the combination was vital to attainment of complete response in Flt3ITD+ve cases exhibiting such Wnt pathway dysregulation.

Original languageEnglish (US)
Pages (from-to)5703-5715
Number of pages13
JournalOncotarget
Volume9
Issue number5
DOIs
StatePublished - Jan 1 2018

Fingerprint

Wnt Signaling Pathway
Mutation
Epigenetic Repression
Histone Deacetylase Inhibitors
Chromatin Assembly and Disassembly
Tumor Suppressor Genes
Epigenomics
Signal Transduction
Down-Regulation
Animal Models
Phenotype
Bortezomib
Therapeutics
vorinostat
sorafenib

Keywords

  • AML
  • Bortezomib
  • Epigenetics
  • Sorafenib
  • Vorinostat

ASJC Scopus subject areas

  • Oncology

Cite this

Consecutive epigenetically-active agent combinations act in ID1-RUNX3-TET2 and HOXA pathways for Flt3ITD+ve AML. / Sayar, Hamid; Liu, Yan; Gao, Rui; Zaid, Mohammad Abu; Cripe, Larry; Weisenbach, Jill; Sargent, Katie J.; Nassiri, Mehdi; Li, Lang; Konig, Heiko; Suvannasankha, Attaya; Pan, Feng; Shanmugam, Rajasubramaniam; Goswami, Chirayu; Kapur, Reuben; Xu, Mingjiang; Scott Boswell, H.

In: Oncotarget, Vol. 9, No. 5, 01.01.2018, p. 5703-5715.

Research output: Contribution to journalArticle

Sayar, H, Liu, Y, Gao, R, Zaid, MA, Cripe, L, Weisenbach, J, Sargent, KJ, Nassiri, M, Li, L, Konig, H, Suvannasankha, A, Pan, F, Shanmugam, R, Goswami, C, Kapur, R, Xu, M & Scott Boswell, H 2018, 'Consecutive epigenetically-active agent combinations act in ID1-RUNX3-TET2 and HOXA pathways for Flt3ITD+ve AML', Oncotarget, vol. 9, no. 5, pp. 5703-5715. https://doi.org/10.18632/oncotarget.23655
Sayar, Hamid ; Liu, Yan ; Gao, Rui ; Zaid, Mohammad Abu ; Cripe, Larry ; Weisenbach, Jill ; Sargent, Katie J. ; Nassiri, Mehdi ; Li, Lang ; Konig, Heiko ; Suvannasankha, Attaya ; Pan, Feng ; Shanmugam, Rajasubramaniam ; Goswami, Chirayu ; Kapur, Reuben ; Xu, Mingjiang ; Scott Boswell, H. / Consecutive epigenetically-active agent combinations act in ID1-RUNX3-TET2 and HOXA pathways for Flt3ITD+ve AML. In: Oncotarget. 2018 ; Vol. 9, No. 5. pp. 5703-5715.
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abstract = "Co-occurrence of Flt3ITD and TET2 mutations provoke an animal model of AML by epigenetic repression of Wnt pathway antagonists, including RUNX3, and by hyperexpression of ID1, encoding Wnt agonist. These affect HOXA over-expression and treatment resistance. A comparable epigenetic phenotype was identified among adult AML patients needing novel intervention. We chose combinations of targeted agents acting on distinct effectors, at the levels of both signal transduction and chromatin remodeling, in relapsed/refractory AML's, including Flt3ITD+ve, described with a signature of repressed tumor suppressor genes, involving Wnt antagonist RUNX3, occurring along with ID1 and HOXA over-expressions. We tracked patient response to combination of Flt3/Raf inhibitor, Sorafenib, and Vorinostat, pan-histone deacetylase inhibitor, without or with added Bortezomib, in consecutive phase I trials. A striking association of rapid objective remissions (near-complete, complete responses) was noted to accompany induced early pharmacodynamic changes within patient blasts in situ, involving these effectors, significantly linking RUNX3/Wnt antagonist de-repression (80{\%}) and ID1 downregulation (85{\%}), to a response, also preceded by profound HOXA9 repression. Response occurred in context of concurrent TET2 mutation/hypomorphy and Flt3ITD+ve mutation (83{\%} of complete responses). Addition of Bortezomib to the combination was vital to attainment of complete response in Flt3ITD+ve cases exhibiting such Wnt pathway dysregulation.",
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