Protein-Protein Interaction Activates and Fuels Leukemia Cell Growth

Findings also show how an experimental monoclonal antibody treatment inhibits growth and spread of cancer

Stained chronic lymphocytic leukemia cells.

Stained chronic lymphocytic leukemia cells.

Building upon previous research, scientists at University of California, San Diego School of Medicine and UC San Diego Moores Cancer report that a protein called Wnt5a acts on a pair of tumor-surface proteins, called ROR1 and ROR2, to accelerate the proliferation and spread of chronic lymphocytic leukemia (CLL) cells, the most common form of blood cancer in adults.

They note, however, that these effects of Wnt5a were blocked by a humanized monoclonal antibody specific for ROR1, called cirmtuzumab (or UC-961), which inhibited the growth and spread of CLL cells in both cell lines and mouse models of leukemia. The findings are published in the December 21, 2015 issue of The Journal of Clinical Investigation.

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Understanding ROR1

ROR1, an oncogene recently discovered on chronic lymphocytic leukemia (CLL) B cells, is being studied by researchers as a potential target for CLL treatment. Dr. Brian Koffman met with Dr. Thomas Kipps, who is researching ROR1, at the 2014 American Society of Clinical Oncology (ASCO) meeting to discuss this oncogene and its potential use in treating CLL.

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Hot on the ROR1 t(r)ail

ROR1 can interact with TCL1 and enhance leukemogenesis in Eμ-TCL1 transgenic mice.

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncoembryonic antigen found on chronic lymphocytic leukemia (CLL) B cells, but not on normal adult tissues. We generated transgenic (Tg) mice with human ROR1 regulated by the murine Ig promoter/enhancer. In contrast to nontransgenic littermates, such animals had B-cell-restricted expression of ROR1 and could develop clonal expansions of ROR1(bright)CD5(+)B220(low) B cells resembling human CLL at ≥ 15 mo of age. Because immune-precipitation and mass spectrometry studies revealed that ROR1 could complex with T-cell leukemia 1 (TCL1) in CLL, we crossed these animals with Eµ-TCL1-Tg (TCL1) mice. Progeny with both transgenes (ROR1 × TCL1) developed CD5(+)B220(low) B-cell lymphocytosis and leukemia at a significantly younger median age than did littermates with either transgene alone. ROR1 × TCL1 leukemia B cells had higher levels of phospho-AKT than TCL1 leukemia cells and expressed high levels of human ROR1, which we also found complexed with TCL1.

Transcriptome analyses revealed that ROR1 × TCL1 leukemia cells had higher expression of subnetworks implicated in embryonic and tumor-cell proliferation, but lower expression of subnetworks involved in cell-cell adhesion or cell death than did TCL1 leukemia cells. ROR1 × TCL1 leukemia cells also had higher proportions of Ki-67-positive cells, lower proportions of cells undergoing spontaneous apoptosis, and produced more aggressive disease upon adoptive transfer than TCL1 leukemia cells. However, treatment with an anti-ROR1 mAb resulted in ROR1 down-modulation, reduced phospho-AKT, and impaired engraftment of ROR1 × TCL1 leukemia cells. Our data demonstrate that ROR1 accelerates development/progression of leukemia and may be targeted for therapy of patients with CLL.

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Developmental Protein Plays a Role in Spread of Cancer

Dr. Thomas Kipps and scientists from his research laboratory at the UC San Diego Moores Cancer Center discover an association between a protein called ROR1 and EMT, a process that occurs during embryogenesis.

Read the above article to learn more!

Stopping the Spread of Cancer

Stopping cancer’s spread: New protein found to control deadly cancer metastasis

Researchers have found a critical element that may explain why some cancers spread farther and faster than others, a discovery that could lead to one of the Holy Grails of cancer treatment: containing the disease.

Scientists from the University of California, San Diego School of Medicine, Dr. Thomas J. Kipps and colleagues,  have identified a protein that seems to serve as a switch, regulating the spread of cancer from the primary tumor to distant spots in the body – a process known as metastasis.  The protein is used by embryo cells during early development, but then disappears from the body after an individual comes out of the womb.

Read more- Fox News Report: Dr. Kipps

ROR1 Antibody