Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome

Matthew T Witkowski, Yifang Hu, Kathryn G Roberts, Judith M. Boer, Mark D McKenzie, Grace Jie Liu, Oliver D. Le Grice, Cedric Tremblay, Margherita Ghisi, Tracy A Willson, Martin A. Horstmann, Ioannis Aifantis, Luisa Cimmino, Seth Frietze, Monique L. den Boer, Charles G Mullighan, Gordon K Smyth, Ross A Dickins

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Genetic alterations disrupting the transcription factor IKZF1 (encoding IKAROS) are associated with poor outcome in B lineage acute lymphoblastic leukemia (B-ALL) and occur in >70% of the high-risk BCR-ABL1+ (Ph+) and Ph-like disease subtypes. To examine IKAROS function in this context, we have developed novel mouse models allowing reversible RNAi-based control of Ikaros expression in established B-ALL in vivo. Notably, leukemias driven by combined BCR-ABL1 expression and Ikaros suppression rapidly regress when endogenous Ikaros is restored, causing sustained disease remission or ablation. Comparison of transcriptional profiles accompanying dynamic Ikaros perturbation in murine B-ALL in vivo with two independent human B-ALL cohorts identified nine evolutionarily conserved IKAROS-repressed genes. Notably, high expression of six of these genes is associated with inferior event-free survival in both patient cohorts. Among them are EMP1, which was recently implicated in B-ALL proliferation and prednisolone resistance, and the novel target CTNND1, encoding P120-catenin. We demonstrate that elevated Ctnnd1 expression contributes to maintenance of murine B-ALL cells with compromised Ikaros function. These results suggest that IKZF1 alterations in B-ALL leads to induction of multiple genes associated with proliferation and treatment resistance, identifying potential new therapeutic targets for high-risk disease.

Original languageEnglish
Pages (from-to)773-791
Number of pages19
JournalJournal of Experimental Medicine
Volume214
Issue number3
DOIs
Publication statusPublished - 6 Mar 2017

Cite this

Witkowski, Matthew T ; Hu, Yifang ; Roberts, Kathryn G ; Boer, Judith M. ; McKenzie, Mark D ; Liu, Grace Jie ; Le Grice, Oliver D. ; Tremblay, Cedric ; Ghisi, Margherita ; Willson, Tracy A ; Horstmann, Martin A. ; Aifantis, Ioannis ; Cimmino, Luisa ; Frietze, Seth ; den Boer, Monique L. ; Mullighan, Charles G ; Smyth, Gordon K ; Dickins, Ross A. / Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome. In: Journal of Experimental Medicine. 2017 ; Vol. 214, No. 3. pp. 773-791.
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title = "Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome",
abstract = "Genetic alterations disrupting the transcription factor IKZF1 (encoding IKAROS) are associated with poor outcome in B lineage acute lymphoblastic leukemia (B-ALL) and occur in >70{\%} of the high-risk BCR-ABL1+ (Ph+) and Ph-like disease subtypes. To examine IKAROS function in this context, we have developed novel mouse models allowing reversible RNAi-based control of Ikaros expression in established B-ALL in vivo. Notably, leukemias driven by combined BCR-ABL1 expression and Ikaros suppression rapidly regress when endogenous Ikaros is restored, causing sustained disease remission or ablation. Comparison of transcriptional profiles accompanying dynamic Ikaros perturbation in murine B-ALL in vivo with two independent human B-ALL cohorts identified nine evolutionarily conserved IKAROS-repressed genes. Notably, high expression of six of these genes is associated with inferior event-free survival in both patient cohorts. Among them are EMP1, which was recently implicated in B-ALL proliferation and prednisolone resistance, and the novel target CTNND1, encoding P120-catenin. We demonstrate that elevated Ctnnd1 expression contributes to maintenance of murine B-ALL cells with compromised Ikaros function. These results suggest that IKZF1 alterations in B-ALL leads to induction of multiple genes associated with proliferation and treatment resistance, identifying potential new therapeutic targets for high-risk disease.",
author = "Witkowski, {Matthew T} and Yifang Hu and Roberts, {Kathryn G} and Boer, {Judith M.} and McKenzie, {Mark D} and Liu, {Grace Jie} and {Le Grice}, {Oliver D.} and Cedric Tremblay and Margherita Ghisi and Willson, {Tracy A} and Horstmann, {Martin A.} and Ioannis Aifantis and Luisa Cimmino and Seth Frietze and {den Boer}, {Monique L.} and Mullighan, {Charles G} and Smyth, {Gordon K} and Dickins, {Ross A}",
year = "2017",
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day = "6",
doi = "10.1084/jem.20160048",
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Witkowski, MT, Hu, Y, Roberts, KG, Boer, JM, McKenzie, MD, Liu, GJ, Le Grice, OD, Tremblay, C, Ghisi, M, Willson, TA, Horstmann, MA, Aifantis, I, Cimmino, L, Frietze, S, den Boer, ML, Mullighan, CG, Smyth, GK & Dickins, RA 2017, 'Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome' Journal of Experimental Medicine, vol. 214, no. 3, pp. 773-791. https://doi.org/10.1084/jem.20160048

Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome. / Witkowski, Matthew T; Hu, Yifang; Roberts, Kathryn G; Boer, Judith M.; McKenzie, Mark D; Liu, Grace Jie; Le Grice, Oliver D.; Tremblay, Cedric; Ghisi, Margherita; Willson, Tracy A; Horstmann, Martin A.; Aifantis, Ioannis; Cimmino, Luisa; Frietze, Seth; den Boer, Monique L.; Mullighan, Charles G; Smyth, Gordon K; Dickins, Ross A.

In: Journal of Experimental Medicine, Vol. 214, No. 3, 06.03.2017, p. 773-791.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome

AU - Witkowski, Matthew T

AU - Hu, Yifang

AU - Roberts, Kathryn G

AU - Boer, Judith M.

AU - McKenzie, Mark D

AU - Liu, Grace Jie

AU - Le Grice, Oliver D.

AU - Tremblay, Cedric

AU - Ghisi, Margherita

AU - Willson, Tracy A

AU - Horstmann, Martin A.

AU - Aifantis, Ioannis

AU - Cimmino, Luisa

AU - Frietze, Seth

AU - den Boer, Monique L.

AU - Mullighan, Charles G

AU - Smyth, Gordon K

AU - Dickins, Ross A

PY - 2017/3/6

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N2 - Genetic alterations disrupting the transcription factor IKZF1 (encoding IKAROS) are associated with poor outcome in B lineage acute lymphoblastic leukemia (B-ALL) and occur in >70% of the high-risk BCR-ABL1+ (Ph+) and Ph-like disease subtypes. To examine IKAROS function in this context, we have developed novel mouse models allowing reversible RNAi-based control of Ikaros expression in established B-ALL in vivo. Notably, leukemias driven by combined BCR-ABL1 expression and Ikaros suppression rapidly regress when endogenous Ikaros is restored, causing sustained disease remission or ablation. Comparison of transcriptional profiles accompanying dynamic Ikaros perturbation in murine B-ALL in vivo with two independent human B-ALL cohorts identified nine evolutionarily conserved IKAROS-repressed genes. Notably, high expression of six of these genes is associated with inferior event-free survival in both patient cohorts. Among them are EMP1, which was recently implicated in B-ALL proliferation and prednisolone resistance, and the novel target CTNND1, encoding P120-catenin. We demonstrate that elevated Ctnnd1 expression contributes to maintenance of murine B-ALL cells with compromised Ikaros function. These results suggest that IKZF1 alterations in B-ALL leads to induction of multiple genes associated with proliferation and treatment resistance, identifying potential new therapeutic targets for high-risk disease.

AB - Genetic alterations disrupting the transcription factor IKZF1 (encoding IKAROS) are associated with poor outcome in B lineage acute lymphoblastic leukemia (B-ALL) and occur in >70% of the high-risk BCR-ABL1+ (Ph+) and Ph-like disease subtypes. To examine IKAROS function in this context, we have developed novel mouse models allowing reversible RNAi-based control of Ikaros expression in established B-ALL in vivo. Notably, leukemias driven by combined BCR-ABL1 expression and Ikaros suppression rapidly regress when endogenous Ikaros is restored, causing sustained disease remission or ablation. Comparison of transcriptional profiles accompanying dynamic Ikaros perturbation in murine B-ALL in vivo with two independent human B-ALL cohorts identified nine evolutionarily conserved IKAROS-repressed genes. Notably, high expression of six of these genes is associated with inferior event-free survival in both patient cohorts. Among them are EMP1, which was recently implicated in B-ALL proliferation and prednisolone resistance, and the novel target CTNND1, encoding P120-catenin. We demonstrate that elevated Ctnnd1 expression contributes to maintenance of murine B-ALL cells with compromised Ikaros function. These results suggest that IKZF1 alterations in B-ALL leads to induction of multiple genes associated with proliferation and treatment resistance, identifying potential new therapeutic targets for high-risk disease.

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