A noncanonical Flt3ITD/NF-κB signaling pathway represses DAPK1 in acute myeloid leukemia

Rajasubramaniam Shanmugam, Padmaja Gade, Annique Wilson-Weekes, Hamid Sayar, Attaya Suvannasankha, Chirayu Goswami, Lang Li, Sushil Gupta, Angelo A. Cardoso, Tareq Al Baghdadi, Katie J. Sargent, Larry Cripe, Dhananjaya V. Kalvakolanu, H. Boswell

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Abstract

Purpose: Death-associated protein kinase 1 (DAPK1), a tumor suppressor, is a rate-limiting effector in an endoplasmic reticulum (ER) stress-dependent apoptotic pathway. Its expression is epigenetically suppressed in several tumors. Amechanistic basis for epigenetic/transcriptional repression of DAPK1 was investigated in certain forms of acute myeloid leukemia (AML) with poor prognosis, which lacked ER stress-induced apoptosis. Experimental Design: Heterogeneous primary AMLs were screened to identify a subgroup with Flt3ITD in which repression of DAPK1, among NF-κB - and c-Jun-responsive genes, was studied. RNA interference knockdown studies were carried out in an Flt3ITD + cell line, MV-4-11, to establish genetic epistasis in the pathway Flt3ITD-TAK1-DAPK1 repression, and chromatin immunoprecipitations were carried out to identify proximate effector proteins, including TAK1-activated p52NF-κB, at the DAPK1 locus. Results: AMLs characterized by normal karyotype with Flt3ITD were found to have 10- to 100-fold lower DAPK1 transcripts normalized to the expression of c-Jun, a transcriptional activator of DAPK1, as compared with a heterogeneous cytogenetic category. In addition, Meis1, a c-Jun-responsive adverse AML prognostic gene signature was measured as control. These Flt3ITD + AMLs overexpress relB, a transcriptional repressor, which forms active heterodimers with p52NF-κB. Chromatin immunoprecipitation assays identified p52NF-κB binding to the DAPK1 promoter together with histone deacetylase 2 (HDAC2) and HDAC6 in the Flt3ITD + human AML cell line MV-4-11. Knockdown of p52NF-κB or its upstream regulator, NF-κB-inducing kinase (NIK), de-repressed DAPK1. DAPK1-repressed primary Flt3ITD + AMLs had selective nuclear activation of p52NF-κB. Conclusions: Flt3ITD promotes a noncanonical pathway via TAK1 and p52NF-κB to suppress DAPK1 in association with HDACs, which explains DAPK1 repression in Flt3ITD + AML.

Original languageEnglish
Pages (from-to)360-369
Number of pages10
JournalClinical Cancer Research
Volume18
Issue number2
DOIs
StatePublished - Jan 15 2012

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Death-Associated Protein Kinases
Acute Myeloid Leukemia
Endoplasmic Reticulum Stress
Chromatin Immunoprecipitation
Epigenetic Repression
Histone Deacetylase 2
Genetic Epistasis
jun Genes
Cell Line
Myeloid Cells
RNA Interference
Karyotype
Cytogenetics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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A noncanonical Flt3ITD/NF-κB signaling pathway represses DAPK1 in acute myeloid leukemia. / Shanmugam, Rajasubramaniam; Gade, Padmaja; Wilson-Weekes, Annique; Sayar, Hamid; Suvannasankha, Attaya; Goswami, Chirayu; Li, Lang; Gupta, Sushil; Cardoso, Angelo A.; Al Baghdadi, Tareq; Sargent, Katie J.; Cripe, Larry; Kalvakolanu, Dhananjaya V.; Boswell, H.

In: Clinical Cancer Research, Vol. 18, No. 2, 15.01.2012, p. 360-369.

Research output: Contribution to journalArticle

Shanmugam, R, Gade, P, Wilson-Weekes, A, Sayar, H, Suvannasankha, A, Goswami, C, Li, L, Gupta, S, Cardoso, AA, Al Baghdadi, T, Sargent, KJ, Cripe, L, Kalvakolanu, DV & Boswell, H 2012, 'A noncanonical Flt3ITD/NF-κB signaling pathway represses DAPK1 in acute myeloid leukemia', Clinical Cancer Research, vol. 18, no. 2, pp. 360-369. https://doi.org/10.1158/1078-0432.CCR-10-3022
Shanmugam, Rajasubramaniam ; Gade, Padmaja ; Wilson-Weekes, Annique ; Sayar, Hamid ; Suvannasankha, Attaya ; Goswami, Chirayu ; Li, Lang ; Gupta, Sushil ; Cardoso, Angelo A. ; Al Baghdadi, Tareq ; Sargent, Katie J. ; Cripe, Larry ; Kalvakolanu, Dhananjaya V. ; Boswell, H. / A noncanonical Flt3ITD/NF-κB signaling pathway represses DAPK1 in acute myeloid leukemia. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 2. pp. 360-369.
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abstract = "Purpose: Death-associated protein kinase 1 (DAPK1), a tumor suppressor, is a rate-limiting effector in an endoplasmic reticulum (ER) stress-dependent apoptotic pathway. Its expression is epigenetically suppressed in several tumors. Amechanistic basis for epigenetic/transcriptional repression of DAPK1 was investigated in certain forms of acute myeloid leukemia (AML) with poor prognosis, which lacked ER stress-induced apoptosis. Experimental Design: Heterogeneous primary AMLs were screened to identify a subgroup with Flt3ITD in which repression of DAPK1, among NF-κB - and c-Jun-responsive genes, was studied. RNA interference knockdown studies were carried out in an Flt3ITD + cell line, MV-4-11, to establish genetic epistasis in the pathway Flt3ITD-TAK1-DAPK1 repression, and chromatin immunoprecipitations were carried out to identify proximate effector proteins, including TAK1-activated p52NF-κB, at the DAPK1 locus. Results: AMLs characterized by normal karyotype with Flt3ITD were found to have 10- to 100-fold lower DAPK1 transcripts normalized to the expression of c-Jun, a transcriptional activator of DAPK1, as compared with a heterogeneous cytogenetic category. In addition, Meis1, a c-Jun-responsive adverse AML prognostic gene signature was measured as control. These Flt3ITD + AMLs overexpress relB, a transcriptional repressor, which forms active heterodimers with p52NF-κB. Chromatin immunoprecipitation assays identified p52NF-κB binding to the DAPK1 promoter together with histone deacetylase 2 (HDAC2) and HDAC6 in the Flt3ITD + human AML cell line MV-4-11. Knockdown of p52NF-κB or its upstream regulator, NF-κB-inducing kinase (NIK), de-repressed DAPK1. DAPK1-repressed primary Flt3ITD + AMLs had selective nuclear activation of p52NF-κB. Conclusions: Flt3ITD promotes a noncanonical pathway via TAK1 and p52NF-κB to suppress DAPK1 in association with HDACs, which explains DAPK1 repression in Flt3ITD + AML.",
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T1 - A noncanonical Flt3ITD/NF-κB signaling pathway represses DAPK1 in acute myeloid leukemia

AU - Shanmugam, Rajasubramaniam

AU - Gade, Padmaja

AU - Wilson-Weekes, Annique

AU - Sayar, Hamid

AU - Suvannasankha, Attaya

AU - Goswami, Chirayu

AU - Li, Lang

AU - Gupta, Sushil

AU - Cardoso, Angelo A.

AU - Al Baghdadi, Tareq

AU - Sargent, Katie J.

AU - Cripe, Larry

AU - Kalvakolanu, Dhananjaya V.

AU - Boswell, H.

PY - 2012/1/15

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N2 - Purpose: Death-associated protein kinase 1 (DAPK1), a tumor suppressor, is a rate-limiting effector in an endoplasmic reticulum (ER) stress-dependent apoptotic pathway. Its expression is epigenetically suppressed in several tumors. Amechanistic basis for epigenetic/transcriptional repression of DAPK1 was investigated in certain forms of acute myeloid leukemia (AML) with poor prognosis, which lacked ER stress-induced apoptosis. Experimental Design: Heterogeneous primary AMLs were screened to identify a subgroup with Flt3ITD in which repression of DAPK1, among NF-κB - and c-Jun-responsive genes, was studied. RNA interference knockdown studies were carried out in an Flt3ITD + cell line, MV-4-11, to establish genetic epistasis in the pathway Flt3ITD-TAK1-DAPK1 repression, and chromatin immunoprecipitations were carried out to identify proximate effector proteins, including TAK1-activated p52NF-κB, at the DAPK1 locus. Results: AMLs characterized by normal karyotype with Flt3ITD were found to have 10- to 100-fold lower DAPK1 transcripts normalized to the expression of c-Jun, a transcriptional activator of DAPK1, as compared with a heterogeneous cytogenetic category. In addition, Meis1, a c-Jun-responsive adverse AML prognostic gene signature was measured as control. These Flt3ITD + AMLs overexpress relB, a transcriptional repressor, which forms active heterodimers with p52NF-κB. Chromatin immunoprecipitation assays identified p52NF-κB binding to the DAPK1 promoter together with histone deacetylase 2 (HDAC2) and HDAC6 in the Flt3ITD + human AML cell line MV-4-11. Knockdown of p52NF-κB or its upstream regulator, NF-κB-inducing kinase (NIK), de-repressed DAPK1. DAPK1-repressed primary Flt3ITD + AMLs had selective nuclear activation of p52NF-κB. Conclusions: Flt3ITD promotes a noncanonical pathway via TAK1 and p52NF-κB to suppress DAPK1 in association with HDACs, which explains DAPK1 repression in Flt3ITD + AML.

AB - Purpose: Death-associated protein kinase 1 (DAPK1), a tumor suppressor, is a rate-limiting effector in an endoplasmic reticulum (ER) stress-dependent apoptotic pathway. Its expression is epigenetically suppressed in several tumors. Amechanistic basis for epigenetic/transcriptional repression of DAPK1 was investigated in certain forms of acute myeloid leukemia (AML) with poor prognosis, which lacked ER stress-induced apoptosis. Experimental Design: Heterogeneous primary AMLs were screened to identify a subgroup with Flt3ITD in which repression of DAPK1, among NF-κB - and c-Jun-responsive genes, was studied. RNA interference knockdown studies were carried out in an Flt3ITD + cell line, MV-4-11, to establish genetic epistasis in the pathway Flt3ITD-TAK1-DAPK1 repression, and chromatin immunoprecipitations were carried out to identify proximate effector proteins, including TAK1-activated p52NF-κB, at the DAPK1 locus. Results: AMLs characterized by normal karyotype with Flt3ITD were found to have 10- to 100-fold lower DAPK1 transcripts normalized to the expression of c-Jun, a transcriptional activator of DAPK1, as compared with a heterogeneous cytogenetic category. In addition, Meis1, a c-Jun-responsive adverse AML prognostic gene signature was measured as control. These Flt3ITD + AMLs overexpress relB, a transcriptional repressor, which forms active heterodimers with p52NF-κB. Chromatin immunoprecipitation assays identified p52NF-κB binding to the DAPK1 promoter together with histone deacetylase 2 (HDAC2) and HDAC6 in the Flt3ITD + human AML cell line MV-4-11. Knockdown of p52NF-κB or its upstream regulator, NF-κB-inducing kinase (NIK), de-repressed DAPK1. DAPK1-repressed primary Flt3ITD + AMLs had selective nuclear activation of p52NF-κB. Conclusions: Flt3ITD promotes a noncanonical pathway via TAK1 and p52NF-κB to suppress DAPK1 in association with HDACs, which explains DAPK1 repression in Flt3ITD + AML.

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