High-level ROR1 associates with accelerated disease progression in chronic lymphocytic leukemia

Bing Cui, Emanuela M. Ghia, Liguang Chen, Laura Z. Rassenti, Christopher DeBoever, George F. Widhopf, Jian Yu, Donna S. Neuberg, William G. Wierda, Kanti R. Rai, Neil Elliot Kay, Jennifer R. Brown, Jeffrey A. Jones, John G. Gribben, Kelly A. Frazer, Thomas J. Kipps

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

ROR1 is an oncoembryonic orphan receptor found on chronic lymphocytic leukemia (CLL) B cells, but not on normal postpartum tissues. ROR1 is a receptor for Wnt5a that may complex with TCL1, a coactivator of AKT that is able to promote development of CLL. We found the CLL cells of a few patients expressed negligible ROR1 (ROR1Neg), but expressed TCL1A at levels comparable to those of samples that expressed ROR1 (ROR1Pos). Transcriptome analyses revealed that ROR1Neg cases generally could be distinguished from those that were ROR1Pos in unsupervised gene-expression clustering analysis. Gene-set enrichment analyses demonstrated that ROR1Neg CLL had lower expression and activation of AKT signaling pathways relative to ROR1Pos CLL, similar to what was noted for leukemia that respectively developed in TCL1 vs ROR1xTCL1 transgenic mice. In contrast to its effect on ROR1Pos CLL, Wnt5a did not enhance the proliferation, chemotaxis, or survival of ROR1Neg CLL. We examined the CLL cells from 1568 patients, which we randomly assigned to a training or validation set of 797 or 771 cases, respectively. Using recursive partitioning, we defined a threshold for ROR1 surface expression that could segregate samples of the training set into ROR1-Hi vs ROR1-Lo subgroups that differed significantly in their median treatment-free survival (TFS). Using this threshold, we found that ROR1-Hi cases had a significantly shorter median TFS and overall survival than ROR1-Lo cases in the validation set. These data demonstrate that expression of ROR1 may promote leukemia-cell activation and survival and enhance disease progression in patients with CLL.

Original languageEnglish (US)
Pages (from-to)2931-2940
Number of pages10
JournalBlood
Volume128
Issue number25
DOIs
StatePublished - Dec 22 2016

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B-Cell Chronic Lymphocytic Leukemia
Disease Progression
Chemical activation
Gene expression
Genes
Cells
Tissue
Survival
Leukemia
Gene Expression Profiling
Chemotaxis
Postpartum Period
Transgenic Mice
Cluster Analysis
Cell Survival
Gene Expression
Therapeutics

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Cui, B., Ghia, E. M., Chen, L., Rassenti, L. Z., DeBoever, C., Widhopf, G. F., ... Kipps, T. J. (2016). High-level ROR1 associates with accelerated disease progression in chronic lymphocytic leukemia. Blood, 128(25), 2931-2940. https://doi.org/10.1182/blood-2016-04-712562

High-level ROR1 associates with accelerated disease progression in chronic lymphocytic leukemia. / Cui, Bing; Ghia, Emanuela M.; Chen, Liguang; Rassenti, Laura Z.; DeBoever, Christopher; Widhopf, George F.; Yu, Jian; Neuberg, Donna S.; Wierda, William G.; Rai, Kanti R.; Kay, Neil Elliot; Brown, Jennifer R.; Jones, Jeffrey A.; Gribben, John G.; Frazer, Kelly A.; Kipps, Thomas J.

In: Blood, Vol. 128, No. 25, 22.12.2016, p. 2931-2940.

Research output: Contribution to journalArticle

Cui, B, Ghia, EM, Chen, L, Rassenti, LZ, DeBoever, C, Widhopf, GF, Yu, J, Neuberg, DS, Wierda, WG, Rai, KR, Kay, NE, Brown, JR, Jones, JA, Gribben, JG, Frazer, KA & Kipps, TJ 2016, 'High-level ROR1 associates with accelerated disease progression in chronic lymphocytic leukemia', Blood, vol. 128, no. 25, pp. 2931-2940. https://doi.org/10.1182/blood-2016-04-712562
Cui B, Ghia EM, Chen L, Rassenti LZ, DeBoever C, Widhopf GF et al. High-level ROR1 associates with accelerated disease progression in chronic lymphocytic leukemia. Blood. 2016 Dec 22;128(25):2931-2940. https://doi.org/10.1182/blood-2016-04-712562
Cui, Bing ; Ghia, Emanuela M. ; Chen, Liguang ; Rassenti, Laura Z. ; DeBoever, Christopher ; Widhopf, George F. ; Yu, Jian ; Neuberg, Donna S. ; Wierda, William G. ; Rai, Kanti R. ; Kay, Neil Elliot ; Brown, Jennifer R. ; Jones, Jeffrey A. ; Gribben, John G. ; Frazer, Kelly A. ; Kipps, Thomas J. / High-level ROR1 associates with accelerated disease progression in chronic lymphocytic leukemia. In: Blood. 2016 ; Vol. 128, No. 25. pp. 2931-2940.
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abstract = "ROR1 is an oncoembryonic orphan receptor found on chronic lymphocytic leukemia (CLL) B cells, but not on normal postpartum tissues. ROR1 is a receptor for Wnt5a that may complex with TCL1, a coactivator of AKT that is able to promote development of CLL. We found the CLL cells of a few patients expressed negligible ROR1 (ROR1Neg), but expressed TCL1A at levels comparable to those of samples that expressed ROR1 (ROR1Pos). Transcriptome analyses revealed that ROR1Neg cases generally could be distinguished from those that were ROR1Pos in unsupervised gene-expression clustering analysis. Gene-set enrichment analyses demonstrated that ROR1Neg CLL had lower expression and activation of AKT signaling pathways relative to ROR1Pos CLL, similar to what was noted for leukemia that respectively developed in TCL1 vs ROR1xTCL1 transgenic mice. In contrast to its effect on ROR1Pos CLL, Wnt5a did not enhance the proliferation, chemotaxis, or survival of ROR1Neg CLL. We examined the CLL cells from 1568 patients, which we randomly assigned to a training or validation set of 797 or 771 cases, respectively. Using recursive partitioning, we defined a threshold for ROR1 surface expression that could segregate samples of the training set into ROR1-Hi vs ROR1-Lo subgroups that differed significantly in their median treatment-free survival (TFS). Using this threshold, we found that ROR1-Hi cases had a significantly shorter median TFS and overall survival than ROR1-Lo cases in the validation set. These data demonstrate that expression of ROR1 may promote leukemia-cell activation and survival and enhance disease progression in patients with CLL.",
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AU - Ghia, Emanuela M.

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AU - DeBoever, Christopher

AU - Widhopf, George F.

AU - Yu, Jian

AU - Neuberg, Donna S.

AU - Wierda, William G.

AU - Rai, Kanti R.

AU - Kay, Neil Elliot

AU - Brown, Jennifer R.

AU - Jones, Jeffrey A.

AU - Gribben, John G.

AU - Frazer, Kelly A.

AU - Kipps, Thomas J.

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