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 language | English |
|---|---|
| Pages (from-to) | 773-791 |
| Number of pages | 19 |
| Journal | Journal of Experimental Medicine |
| Volume | 214 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 6 Mar 2017 |
Cite this
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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 journal › Article › Research › peer-review
TY - JOUR
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
Y1 - 2017/3/6
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.
UR - http://www.scopus.com/inward/record.url?scp=85021868943&partnerID=8YFLogxK
U2 - 10.1084/jem.20160048
DO - 10.1084/jem.20160048
M3 - Article
VL - 214
SP - 773
EP - 791
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 3
ER -