High-level ROR1 associates with accelerated disease progression in chronic lymphocytic leukemia.
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 ROR1Negcases generally could be distinguished from those that were ROR1Posin unsupervised gene-expression clustering analysis. Gene-set enrichment analyses demonstrated that ROR1NegCLL had lower expression and activation of AKT signaling pathways relative to ROR1PosCLL, similar to what was noted for leukemia that respectively developed in TCL1 vs ROR1xTCL1 transgenic mice. In contrast to its effect on ROR1PosCLL, Wnt5a did not enhance the proliferation, chemotaxis, or survival of ROR1NegCLL. 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.
Department of Medicine, Moores Cancer Center, University of California, San Diego, San Diego, CA.|State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Bing
B
Cui
Department of Medicine, Moores Cancer Center, University of California, San Diego, San Diego, CA.
Emanuela M
EM
Ghia
Department of Medicine, Moores Cancer Center, University of California, San Diego, San Diego, CA.
Liguang
L
Chen
Department of Medicine, Moores Cancer Center, University of California, San Diego, San Diego, CA.
Laura Z
LZ
Rassenti
Bioinformatics and Systems Biology, University of California, San Diego, San Diego, CA.
Christopher
0000-0002-1901-2576
C
DeBoever
Department of Medicine, Moores Cancer Center, University of California, San Diego, San Diego, CA.
George F
GF
Widhopf
Department of Medicine, Moores Cancer Center, University of California, San Diego, San Diego, CA.
Jian
J
Yu
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard University, Boston, MA.
Donna S
0000-0003-2566-3145
DS
Neuberg
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.
William G
WG
Wierda
Department of Medicine, Hofstra North Shore-Long Island Jewish School of Medicine, Hempstead, NY.
Kanti R
0000-0002-5804-2823
KR
Rai
Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, MN.
Neil E
0000-0002-5951-5055
NE
Kay
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard University, Boston, MA.
Jennifer R
JR
Brown
Division of Hematology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH.
Jeffrey A
JA
Jones
Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK; and.
John G
JG
Gribben
Moores Cancer Center, Department of Pediatrics and Rady Children's Hospital, Institute for Genomic Medicine, Chronic Lymphocytic Leukemia Research Consortium, University of California, San Diego, San Diego, CA.
Kelly A
0000-0002-6060-8902
KA
Frazer
Department of Medicine, Moores Cancer Center, University of California, San Diego, San Diego, CA.
Thomas J
TJ
Kipps
D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D018450:Disease Progression; D018572:Disease-Free Survival; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D053263:Gene Regulatory Networks; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology*; D015999:Multivariate Analysis; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism*
D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; C078716:ROR1 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors