Chronic Lymphocytic Leukemia Research Consortium

San Diego, CA, United States

Chronic Lymphocytic Leukemia Research Consortium

San Diego, CA, United States
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Ghia E.M.,University of California at San Diego | Ghia E.M.,Chronic Lymphocytic Leukemia Research Consortium | Widhopf II G.F.,University of California at San Diego | Widhopf II G.F.,Chronic Lymphocytic Leukemia Research Consortium | And 4 more authors.
Journal of Immunology | Year: 2011

Chronic lymphocytic leukemia (CLL) cells that use IgH encoded by IGHV3-21 and that have a particular stereotypic third CDR (HCDR3), DANGMDV (motif-1), almost invariably express Ig L chains (IgL) encoded by IGLV3-21, whereas CLL that use IGHV3-21-encoded IgH with another stereotypic HCDR3, DPSFYSSSWTLFDY (motif-2), invariably express κ-IgL encoded by IGKV3-20. This nonstochastic pairing could reflect steric factors that preclude these IgH from pairing with other IgL or selection for an Ig with a particular Ag-binding activity. We generated rIg with IGHV3-21-encoded IgH with HCDR3 motif-1 or -2 and IgL encoded by IGKV3-20 or IGLV3-21. Each IgH paired equally well with matched or mismatched κ- or λ-IgL to form functional Ig, which we screened for binding to an array of different Ags. Ig with IGLV3-21-encoded λ-IgL could bind with an affinity of ∼2 × 10-6 M to protein L, a cell-wall protein of Peptostreptococcus magnus, independent of the IgH, indicating that protein L is a superantigen for IGLV3-21-encoded λ-IgL. We also detected Ig binding to cofilin, a highly conserved actin-binding protein. However, cofilin binding was independent of native pairing of IgH and IgL and was not specific for Ig with IgH encoded by IGHV3-21. We conclude that steric factors or the binding activity for protein L or cofilin cannot account for the nonstochastic pairing of IgH and IgL observed for the stereotypic Ig made by CLL cells that express IGHV3-21. Copyright © 2011 by The American Association of Immunologists, Inc.

Veronese A.,University of Chieti Pescara | Pepe F.,University of Chieti Pescara | Chiacchia J.,University of Chieti Pescara | Pagotto S.,University of Chieti Pescara | And 20 more authors.
Leukemia | Year: 2015

Deregulation of the miR-15a/16-1 cluster has a key role in the pathogenesis of chronic lymphocytic leukemia (CLL), a clinically heterogeneous disease with indolent and aggressive forms. The miR-15a/16-1 locus is located at 13q14, the most frequently deleted region in CLL. Starting from functional investigations of a rare SNP upstream the miR cluster, we identified a novel allele-specific mechanism that exploits a cryptic activator region to recruit the RNA polymerase III for miR-15a/16-1 transcription. This regulation of the miR-15a/16-locus is independent of the DLEU2 host gene, which is often transcribed monoallellically by RPII. We found that normally one allele of miR-15a/16-1 is transcribed by RNAPII, the other one by RNAPIII. In our subset of CLL patients harboring 13q14 deletions, exclusive RNA polymerase III (RPIII)-driven transcription of the miR-15a/16-1 was the consequence of loss of the RPII-regulated allele and correlated with high expression of the poor prognostic marker ZAP70 (P=0.019). Thus, our findings point to a novel biological process, characterized by double allele-specific transcriptional regulation of the miR-15a/16-1 locus by alternative mechanisms. Differential usage of these mechanisms may distinguish at onset aggressive from indolent forms of CLL. This provides a basis for the clinical heterogeneity of the CLL patients carrying 13q14 deletions. © 2015 Macmillan Publishers Limited.

Visone R.,Ohio State University | Veronese A.,Ohio State University | Rassenti L.Z.,University of California at San Diego | Rassenti L.Z.,Chronic Lymphocytic Leukemia Research Consortium | And 9 more authors.
Blood | Year: 2011

MicroRNAs play a crucial role in chronic lymphocytic leukemia. We investigated whether microRNAs can discriminate patients with a progressive disease from patients with a stable disease. We analyzed microRNA expression on leukemic cells isolated from 358 sequential samples of 114 patients with either stable or progressive disease. We found that during the course of the disease the expression values of miR-181b, the most dysregulated microRNA, decreased in samples of patients with a progressive (P < .001, training and validation sets) but not in samples of patients with a stable disease (P = .3, training set; P = .2, validation set) over time. A drop of ≥ 50% between sequential samples and/or a miR-181b value ≤ 0.005 at the starting time point were significant to differentiate progressive from stable disease (P = .004, training set; P < .001, validation set). These parameters were associated with high risk of requiring treatment (risk ratio, 5.8; 95% confidence interval, 2.5-14.9). We also observed that miR-181b targets Mcl-1 protein and that the decrease of its expression inversely correlated with increased protein levels of MCL1 and BCL2 target genes. We conclude that parameters defined on the basis of the miR-181b expression values specify disease progression in chronic lymphocytic leukemia and are associated with clinical outcome. © 2011 by The American Society of Hematology.

Sattari A.,Ohio State University | Sattari A.,University of Verona | Sattari A.,Islamic Azad University at Gorgan | Siddiqui H.,Ohio State University | And 8 more authors.
Oncotarget | Year: 2016

Long noncoding RNAs (lncRNAs) are non-proten-coding transcripts of more than 200 nucleotides generated by RNA polymerase II and their expressions are tightly regulated in cell type specific- and/or cellular differential stage specificmanner. MIAT, originally isolated as a candidate gene for myocardial infarction, encodes lncRNA (termed MIAT). Here, we determined the expression level of MIAT in established leukemia/lymphoma cell lines and found its upregulation in lymphoid but not in myeloid cell lineage with mature B cell phenotype. MIAT expression level was further determined in chronic lymphocytic leukemias (CLL), characterized by expansion of leukemic cells with mature B phenotype, to demonstrate relatively high occurrence of MIAT upregulation in aggressive form of CLL carrying either 17p-deletion, 11q-deletion, or Trisomy 12 over indolent form carrying 13p-deletion. Furthermore, we show that MIAT constitutes a regulatory loop with OCT4 in malignant mature B cell, as was previously reported in mouse pulripotent stem cell, and that both molecules are essential for cell survival.

News Article | December 9, 2016

RIVERSIDE, Calif. - Cancer researchers and drug companies may have been too quick to ignore a promising line of inquiry that targets a specific cell protein, according to a research team led by a biomedical scientist in the School of Medicine at the University of California, Riverside. Every cell in our body produces pro-death proteins and anti-death proteins, which interact with each other, negating each other's function. A healthy balance between them is a natural process. A damaged cell, for example, produces more pro-death proteins than anti-death proteins, resulting in a natural elimination of the diseased cell, a process also known as apoptosis. Pro- and anti-death proteins are therefore termed pro- and anti-apoptotic proteins, respectively. In cancer cells, genetic alterations result in an overproduction of anti-apoptotic proteins. As a result, such cancer cells keep surviving and become resistant to treatment (chemotherapy or radiation) instead of dying, resulting in uncontrolled proliferation. Anti-apoptotic proteins, therefore, have been the target for developing drugs that restore apoptosis in cancer cells. Bcl-2 is a member of a family of six anti-apoptotic proteins. It is the most studied of the six proteins, and the drug Venetoclax, approved by the Food and Drug Administration in 2016, targets it. But what if cancer cells develop resistance to this drug, which targets only one anti-death protein? Based on studies using mouse proteins, academics and pharmaceutical companies have been focusing on the next anti-apoptotic protein in the line-up: Mcl-1. When cancer cells are exposed to chemotherapy, radiation or even immuno-therapy, pro-apoptotic signals, such as the toxin NOXA, are produced in the cell that result in cancer cell death. Two anti-apoptotic proteins, Mcl-1 and Bfl-1, are known to oppose the effects of NOXA. Hence, inhibitors of these two anti-apoptotic proteins may complement Venetoclax in restoring apoptosis in cancer cells. Most efforts have been concentrated only on Mcl-1, because studies with mouse proteins have shown that NOXA interacts very tightly with Mcl-1 and sequesters it. But a team of researchers led by Maurizio Pellecchia at UC Riverside cautions that the focus needs to be on a different anti-apoptotic protein: Bfl-1. "What we discovered is that while these early studies done with the mouse versions of the proteins NOXA, Mcl-1, and Bfl-1 were correct, these do not entirely apply to human proteins," said Pellecchia, a professor of biomedical sciences and the Daniel Hays Endowed Chair in Cancer Research. "This is because human NOXA and Bfl-1 are different from their mouse counterparts. Indeed, we found that when we profiled human NOXA against human anti-apoptotic proteins, the highest affinity was for Bfl-1, and not for Mcl-1, making Bfl-1 a much more relevant drug target than previously assumed." Pellecchia's lab found that NOXA interacts with Bfl-1 through a unique chemical bond (a "disulfide bridge" between unique sulfur atoms present on each protein) not seen in the other five anti-apoptotic proteins. "Understanding how NOXA interacts with Bfl-1 allowed us to devise in the lab a surrogate NOXA-like molecule that very tightly and permanently binds and inhibits Bfl-1," Pellecchia said. "In proof-of-concept studies with cells from patients affected by chronic lymphocytic leukemia that are resistant to chemotherapy, we showed that if we block Bfl-1 with this innovative inhibitor, the cells begin to die in response to treatment." The research advocates strongly for focusing on Bfl-1 as a drug target. "Academics and pharmaceutical companies are spending considerable amount of effort and resources in finding antagonists to Mcl-1," Pellecchia said. "While these agents are surely useful in certain conditions that are exacerbated by over-production of Mcl-1, we have shown that more focus on Bfl-1 is warranted. Our research provides new insights on the mechanisms of cancer resistance to chemotherapy, suggesting Bfl-1 as a viable drug target, and also provides a direct path on how to develop Bfl-1-targeting drugs." The research was supported by the National Institutes of Health, the Chronic Lymphocytic Leukemia Research Consortium, the UC San Diego Foundation Blood Cancer Research Fund and the Bennett Family Foundation. Pellecchia was joined in the research by Elisa Barile (first author of the research paper), Guya D. Marconi, Surya K. De, Carlo Baggio, Luca Gambini, and Ahmed F. Salem at UCR; and Manoj K. Kashyap, Januario E. Castro, and Thomas J. Kipps at UC San Diego. Baggio and Gambini are postdoctoral scholars in Pellecchia's lab; De and Salem are project scientists in his lab; Barile and Marconi are currently at UC San Diego. The University of California, Riverside (http://www. ) is a doctoral research university, a living laboratory for groundbreaking exploration of issues critical to Inland Southern California, the state and communities around the world. Reflecting California's diverse culture, UCR's enrollment is now nearly 23,000 students. The campus opened a medical school in 2013 and has reached the heart of the Coachella Valley by way of the UCR Palm Desert Center. The campus has an annual statewide economic impact of more than $1 billion. A broadcast studio with fiber cable to the AT&T Hollywood hub is available for live or taped interviews. UCR also has ISDN for radio interviews. To learn more, call (951) UCR-NEWS.

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