Activated Notch counteracts Ikaros tumor suppression in mouse and human T-cell acute lymphoblastic leukemia

Matthew T Witkowski, Luisa Cimmino, Yifang Hu, Thomas Trimarchi, Hiromi Tagoh, Mark D McKenzie, Sarah A Best, Laura Tuohey, Tracy A Willson, Stewart L Nutt, Meinrad Busslinger, Ioannis Aifantis, Gordon K Smyth, Ross Alexander Dickins

Research output: Contribution to journalArticleResearchpeer-review

15 Citations (Scopus)

Abstract

Activating NOTCH1 mutations occur in 60 of human T-cell acute lymphoblastic leukemias (T-ALLs), and mutations disrupting the transcription factor IKZF1 (IKAROS) occur in 5 of cases. To investigate the regulatory interplay between these driver genes, we have used a novel transgenic RNA interference mouse model to produce primary T-ALLs driven by reversible Ikaros knockdown. Restoring endogenous Ikaros expression in established T-ALL in vivo acutely represses Notch1 and its oncogenic target genes including Myc, and in multiple primary leukemias causes disease regression. In contrast, leukemias expressing high levels of endogenous or engineered forms of activated intracellular Notch1 (ICN1) resembling those found in human T-ALL rapidly relapse following Ikaros restoration, indicating that ICN1 functionally antagonizes Ikaros in established disease. Furthermore, we find that IKAROS mRNA expression is significantly reduced in a cohort of primary human T-ALL patient samples with activating NOTCH1/FBXW7 mutations, but is upregulated upon acute inhibition of aberrant NOTCH signaling across a panel of human T-ALL cell lines. These results demonstrate for the first time that aberrant NOTCH activity compromises IKAROS function in mouse and human T-ALL, and provide a potential explanation for the relative infrequency of IKAROS gene mutations in human T-ALL. ? 2015 Macmillan Publishers Limited.
Original languageEnglish
Pages (from-to)1301 - 1311
Number of pages11
JournalLeukemia
Volume29
DOIs
Publication statusPublished - 2015
Externally publishedYes

Cite this

Witkowski, Matthew T ; Cimmino, Luisa ; Hu, Yifang ; Trimarchi, Thomas ; Tagoh, Hiromi ; McKenzie, Mark D ; Best, Sarah A ; Tuohey, Laura ; Willson, Tracy A ; Nutt, Stewart L ; Busslinger, Meinrad ; Aifantis, Ioannis ; Smyth, Gordon K ; Dickins, Ross Alexander. / Activated Notch counteracts Ikaros tumor suppression in mouse and human T-cell acute lymphoblastic leukemia. In: Leukemia. 2015 ; Vol. 29. pp. 1301 - 1311.
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title = "Activated Notch counteracts Ikaros tumor suppression in mouse and human T-cell acute lymphoblastic leukemia",
abstract = "Activating NOTCH1 mutations occur in 60 of human T-cell acute lymphoblastic leukemias (T-ALLs), and mutations disrupting the transcription factor IKZF1 (IKAROS) occur in 5 of cases. To investigate the regulatory interplay between these driver genes, we have used a novel transgenic RNA interference mouse model to produce primary T-ALLs driven by reversible Ikaros knockdown. Restoring endogenous Ikaros expression in established T-ALL in vivo acutely represses Notch1 and its oncogenic target genes including Myc, and in multiple primary leukemias causes disease regression. In contrast, leukemias expressing high levels of endogenous or engineered forms of activated intracellular Notch1 (ICN1) resembling those found in human T-ALL rapidly relapse following Ikaros restoration, indicating that ICN1 functionally antagonizes Ikaros in established disease. Furthermore, we find that IKAROS mRNA expression is significantly reduced in a cohort of primary human T-ALL patient samples with activating NOTCH1/FBXW7 mutations, but is upregulated upon acute inhibition of aberrant NOTCH signaling across a panel of human T-ALL cell lines. These results demonstrate for the first time that aberrant NOTCH activity compromises IKAROS function in mouse and human T-ALL, and provide a potential explanation for the relative infrequency of IKAROS gene mutations in human T-ALL. ? 2015 Macmillan Publishers Limited.",
author = "Witkowski, {Matthew T} and Luisa Cimmino and Yifang Hu and Thomas Trimarchi and Hiromi Tagoh and McKenzie, {Mark D} and Best, {Sarah A} and Laura Tuohey and Willson, {Tracy A} and Nutt, {Stewart L} and Meinrad Busslinger and Ioannis Aifantis and Smyth, {Gordon K} and Dickins, {Ross Alexander}",
year = "2015",
doi = "10.1038/leu.2015.27",
language = "English",
volume = "29",
pages = "1301 -- 1311",
journal = "Leukemia",
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Witkowski, MT, Cimmino, L, Hu, Y, Trimarchi, T, Tagoh, H, McKenzie, MD, Best, SA, Tuohey, L, Willson, TA, Nutt, SL, Busslinger, M, Aifantis, I, Smyth, GK & Dickins, RA 2015, 'Activated Notch counteracts Ikaros tumor suppression in mouse and human T-cell acute lymphoblastic leukemia', Leukemia, vol. 29, pp. 1301 - 1311. https://doi.org/10.1038/leu.2015.27

Activated Notch counteracts Ikaros tumor suppression in mouse and human T-cell acute lymphoblastic leukemia. / Witkowski, Matthew T; Cimmino, Luisa; Hu, Yifang; Trimarchi, Thomas; Tagoh, Hiromi; McKenzie, Mark D; Best, Sarah A; Tuohey, Laura; Willson, Tracy A; Nutt, Stewart L; Busslinger, Meinrad; Aifantis, Ioannis; Smyth, Gordon K; Dickins, Ross Alexander.

In: Leukemia, Vol. 29, 2015, p. 1301 - 1311.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Activated Notch counteracts Ikaros tumor suppression in mouse and human T-cell acute lymphoblastic leukemia

AU - Witkowski, Matthew T

AU - Cimmino, Luisa

AU - Hu, Yifang

AU - Trimarchi, Thomas

AU - Tagoh, Hiromi

AU - McKenzie, Mark D

AU - Best, Sarah A

AU - Tuohey, Laura

AU - Willson, Tracy A

AU - Nutt, Stewart L

AU - Busslinger, Meinrad

AU - Aifantis, Ioannis

AU - Smyth, Gordon K

AU - Dickins, Ross Alexander

PY - 2015

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N2 - Activating NOTCH1 mutations occur in 60 of human T-cell acute lymphoblastic leukemias (T-ALLs), and mutations disrupting the transcription factor IKZF1 (IKAROS) occur in 5 of cases. To investigate the regulatory interplay between these driver genes, we have used a novel transgenic RNA interference mouse model to produce primary T-ALLs driven by reversible Ikaros knockdown. Restoring endogenous Ikaros expression in established T-ALL in vivo acutely represses Notch1 and its oncogenic target genes including Myc, and in multiple primary leukemias causes disease regression. In contrast, leukemias expressing high levels of endogenous or engineered forms of activated intracellular Notch1 (ICN1) resembling those found in human T-ALL rapidly relapse following Ikaros restoration, indicating that ICN1 functionally antagonizes Ikaros in established disease. Furthermore, we find that IKAROS mRNA expression is significantly reduced in a cohort of primary human T-ALL patient samples with activating NOTCH1/FBXW7 mutations, but is upregulated upon acute inhibition of aberrant NOTCH signaling across a panel of human T-ALL cell lines. These results demonstrate for the first time that aberrant NOTCH activity compromises IKAROS function in mouse and human T-ALL, and provide a potential explanation for the relative infrequency of IKAROS gene mutations in human T-ALL. ? 2015 Macmillan Publishers Limited.

AB - Activating NOTCH1 mutations occur in 60 of human T-cell acute lymphoblastic leukemias (T-ALLs), and mutations disrupting the transcription factor IKZF1 (IKAROS) occur in 5 of cases. To investigate the regulatory interplay between these driver genes, we have used a novel transgenic RNA interference mouse model to produce primary T-ALLs driven by reversible Ikaros knockdown. Restoring endogenous Ikaros expression in established T-ALL in vivo acutely represses Notch1 and its oncogenic target genes including Myc, and in multiple primary leukemias causes disease regression. In contrast, leukemias expressing high levels of endogenous or engineered forms of activated intracellular Notch1 (ICN1) resembling those found in human T-ALL rapidly relapse following Ikaros restoration, indicating that ICN1 functionally antagonizes Ikaros in established disease. Furthermore, we find that IKAROS mRNA expression is significantly reduced in a cohort of primary human T-ALL patient samples with activating NOTCH1/FBXW7 mutations, but is upregulated upon acute inhibition of aberrant NOTCH signaling across a panel of human T-ALL cell lines. These results demonstrate for the first time that aberrant NOTCH activity compromises IKAROS function in mouse and human T-ALL, and provide a potential explanation for the relative infrequency of IKAROS gene mutations in human T-ALL. ? 2015 Macmillan Publishers Limited.

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