New Computer Program Can Help Uncover Hidden Genomic Alterations that Drive Cancers

Cancer is rarely the result of a single mutation in a single gene. Rather, tumors arise from the complex interplay between any number of mutually exclusive abnormal changes in the genome, the combinations of which can be unique to each individual patient. To better characterize the functional context of genomic variations in cancer, researchers at University of California San Diego School of Medicine and the Broad Institute developed a new computer algorithm they call REVEALER.

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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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Cirmtuzumab: Here About the Promising New Therapy

Researchers at UC San Diego are developing a new drug to treat CLL. The drug, cirmutuzumab, is an antibody designed to attach to a protein on the surface of CLL cells. Researchers hope that this process will block cancerous cell growth and survival. Right now, cirmtuzumab is being tested for its safety and effectiveness in humans in a Phase One clinical trial.  “A brand new way to target and kill blood cancer,” WNDU, features Thomas Kipps, MD, PhD.
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The Role of a NOTCH1 Mutation for CLL Patients

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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Hitting a CLL Treatment “Home Run”

As more chronic lymphocytic leukemia CLL treatments are approved, with many more in development, are researchers closer to hitting a “home run” in treating the disease? Patient advocate Dr. Brian Koffman met with CLL expert Dr. Thomas Kipps at ASCO 2014 to explore emerging therapies and the goal for patients to achieve deep remission.

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PCR duplicates in deep sequencing experiments and potential biasing

Published on the August 7th (2014) in the journal of Genome Biology:

Accurate allele frequencies are important for measuring subclonal heterogeneity and
clonal evolution. Deep-targeted sequencing data can contain PCR duplicates, inflating perceived read depth. Here we adapted the Illumina TruSeq Custom Amplicon kit to include single molecule tagging (SMT) and show that SMT-identified duplicates arise from PCR. We demonstrate that retention of PCR duplicate reads can imply clonal evolution when none exists, while their removal effectively controls the false positivhiseqe rate. Additionally, PCR duplicates alter estimates of subclonal heterogeneity in tumor samples. Our method simplifies PCR duplicate identification and emphasizes their removal in studies of tumor heterogeneity and clonal evolution.

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Lenalidomide inhibits the proliferation of chronic lymphocytic leukemia cells via a cereblon/p21WAF1/Cip1-dependent mechanism independent of functional p53.

Lenalidomide has demonstrated clinical activity in patients with chronic lymphocytic leukemia (CLL), even though it is not cytotoxic for primary CLL cells in vitro. We examined the direct effect of lenalidomide on CLL-cell proliferation induced by CD154-expressing accessory cells in media containing interleukin (IL)-4 and IL-10. Treatment with lenalidomide significantly inhibited CLL-cell proliferation, an effect that was associated with the p53-independent upregulation of the cyclin-dependent kinase inhibitor p21WAF1/Cip1 (p21). Silencing p21 with small interfering RNA (siRNA) impaired the capacity of lenalidomide to inhibit CLL-cell proliferation. Silencing cereblon (CRBN), a known molecular target of lenalidomide, impaired the capacity of lenalidomide to induce expression of p21, inhibit CD154-induced CLL-cell proliferation, or enhance the degradation of Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3).

We isolated CLL cells from the blood of patients before and after short-term treatment with low-dose lenalidomide (5 mg per day) and found the leukemia cells also were induced to express p21 in vivo. These results indicate that lenalidomide can directly inhibit proliferation of CLL cells in a CRBN/p21-dependent, but p53-independent, manner at concentrations achievable in vivo, potentially contributing to the capacity of this drug to inhibit disease-progression in patients with CLL.