FcRH Expression and Biological Potential in B-Cell Chronic Lymphocytic Leukemia

Randall S. Davis, M.D.

University of Alabama at Birmingham

Funded in December, 2004: $300000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . SELECTED PUBLICATIONS .

LAY SUMMARY

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Identifying Markers for Diagnosing Subtypes of Chronic Lymphocytic Leukemia

This study will determine whether specific markers can differentiate between two types of genetically determined B-cell chronic lymphocytic leukemia (B-CLL). If so, the markers could determine whether a patient has the indolent or aggressive form, so that appropriate therapies can be initiated early. Moreover, the research may lead to identification of new therapeutic targets.

B-CLL is an incurable form of leukemia, in which the body's immune B-cells often become self-reactive. In the indolent form, the self-reactive B cells accumulate in bone marrow and peripheral blood over a protracted period. In the aggressive form, the self-reactive B cells infiltrate lymph organs and produce progressive immunodeficiency and autoimmune disease. The two types differ in the mutation of a specific region of their genes. Prior studies have identified genetic markers that distinguish the indolent from aggressive types, but this molecular analysis is costly and technically difficult, and has not led to advances in B-CLL therapies. The Alabama researchers have identified a marker that may address all three of these challenges. The marker is within a family of five receptors that regulate the expression of cells that evolve into immune B cells. These genes have been found in all B-CLL patients. The researchers have found evidence that one of the five receptors is expressed in a subpopulation of "memory" B cells that may be responsible for the autoimmune response in B-CLL. They also have found initial evidence that the receptors may have a signaling abnormality. The investigators hypothesize that one of the five receptors is associated with all B-CLL patients and that expression of two other receptors correlate only with the indolent form.

They will see if this is the case, first by comparing B-CLL patients with healthy controls, and then by comparing receptors found in patients with indolent versus aggressive B-CLL. If the researchers' hypotheses are correct, these receptors would become markers for diagnosing patients and differentiating between the two types of disease. Additionally, the investigators will develop initial evidence of whether there is a signaling defect in the receptor. This eventually may lead to development of new types of therapies aimed at correcting the receptors signaling problem.

Significance: The research may produce a new diagnostic and prognostic marker to differentiate indolent B-CLL from the aggressive form, enabling physicians to select appropriate therapies at the outset. Moreover, the research may unearth new information on the role of these genes in autoimmunity and other malignancies of B cell origin.

ABSTRACT

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FcRH Expression and Biological Potential in B-Cell Chronic Lymphocytic Leukemia

B cell chronic lymphocytic leukemia (B-CLL) is an incurable malignancy with two characterized subsets that differ in the mutation status of their heavy-chain variable region (IgVH) genes, but phenotypically and transcriptionally resemble memory B lineage cells. The correlation of ZAP-70 over-expression and several other less accurate markers with the presence or absence of IgVH somatic hypermutation has enabled the stratification of patients into indolent or more aggressive cohorts. However, the functional implications of these new findings, the underlying biological defect(s), and true cellular origin of the malignant clone remain incompletely understood. Thus, the characterization of new markers for biological understanding, diagnosis, subtyping, and, treatment would help improve the overall care of patients afflicted with this lymphoproliferative disorder. The recent identification of a family of Fc receptor homologs (FcRH1-5) with specific B cell expression opens a new area for study in human immunology, autoimmunity, and malignancy. Given their B cell specific expression patterns and immunoregulatory potential, we hypothesize that FcRH1-5 may provide excellent diagnostic and therapeutic markers for human malignancies of B cell origin and could help to unravel fundamental defects contributing to their pathogenesis.

INVESTIGATOR BIOGRAPHIES

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Randall S. Davis, M.D.

A graduate of Boston University in Boston, Massachusetts, Dr. Davis completed medical school at the University of Alabama School of Medicine (UASOM), where he also served his internship, residency, and the ABIM academic subspecialty research fellowship clinical investigator pathway in Hematology/Oncology. He is Assistant Professor of Medicine and Microbiology, with appointments in Developmental and Clinical Immunology and Hematology/Oncology. He is board certified in Internal Medicine and Hematology. His clinical interests center on lymphoproliferative disorders and B-CLL in particular.

SELECTED PUBLICATIONS

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Li F.J., Ding S., Pan J., Shakhmatov M.A., Kashentseva E., Wu J., Li Y., Soong S.J., Chiorazzi N., and Davis R.S.   FCRL2 expression predicts IGHV mutation status and clinical progression in chronic lymphocytic leukemia. Blood. 2008 Jul 1;112(1):179-87.

Davis, R.S. Fc Receptor Homologs (2007) Ann. Rev. Immunol. 25:525-60.

Ehrhardt G.R., Leu C.M., Zhang S., Aksu G., Jackson T., Haga C., Hsu J.T., Schreeder D.M., Davis R.S., and Cooper M.D.   Fc receptor-like proteins (FCRL): immunomodulators of B cell function.  Adv Exp Med Biol. 2007;596:155-62.

Won W.J., Foote J.B., Odom M., Pan J., Kearney J.F., and Davis R.S.  Fc receptor homolog 3 is a novel immunoregulatory marker of marginal zone and B1 B cells.  J Immunol. 2006 Nov 15;177(10):6815-23.

Maltais L.J., Lovering R.C., Taranin A.V., Ravetch J.V., Dalla-Favera R., Burrows P.D., Cooper M.D., and Davis R.S.  New nomenclature for Fc receptor-like molecules.  Nat Immunol. 2006 May;7(5):431-2.