Rajendra N. Damle, PhD

Unlike other terminally differentiated cells of the immune system, lymphocytes possess the ability to respond to external stimuli and differentiate into functionally distinct cells. The strength of the activating signal and accessory signals derived from the microenvironment govern outcomes of B cell activation that range from increased protein phosphorylation and cell proliferation, to differentiation into antibody producing cells or programmed cell death of the activated cells. The laboratory focuses on lymphocyte signaling and its outcomes pertaining to the immunobiology of B lymphocyte subsets from normal individuals and CLL patients. We reported intraclonal differences in expression of cell activation markers among CLL cells in the past. Recently we found evidence for differential cell cycling and induction of the activity of the enzyme- Telomerase (known as a cell immortality enzyme) among subclones, identified by their expression or not of a cell surface molecule–CD38. Using reagents that simulate molecules that would bind to the B cell receptor or Toll-like receptors and therefore might activate B cells in vivo, the laboratory is currently involved in determining differences in outcomes of signaling in B cells from CLL patients grouped by their Ig V gene mutation status and from B cell subpopulations isolated from normal elderly individuals.

The phosphatidyl-inositol 3 kinase/Akt pathway has been implicated in BCR-mediated signal transduction of normal and CLL-B cells. Recently described FOXO transcription factors are key downstream molecules in this pathway and exhibit an anti-proliferative effect on immune cells while maintaining their homeostasis. Our initial studies indicate that BCR-mediated activation of CLL and normal B cells results in phosphorylation-induced inactivation of FOXO molecules and is accompanied with increased survival and proliferation of activated cells. Our goal is to identify intermediates in the BCR- and TLR- mediated signal transduction pathways that are associated with FOXO molecules, with an aim of translating the knowledge obtained in this process to using specific pharmacological inhibitors of these intermediates for effectively down-modulating the slow cell cycling in CLL patients.

Soluble mediators such as cytokines and chemokines are crucial to regulating cellular homeostasis of normal and cancer cells. In addition cell-cell interactions with activated T cells or stromal cells provide survival signals to differentiating B cells. Studies in the laboratory involve analysis of chemokine receptors CXCR3, CXCR4, CCR4, etc. as expressed by various sub-clones of CLL cells from different tissue sources-eg. blood vs bone marrow. The combined effect of BCR, TLR and chemokine signals on cellular outcomes including their effect on telomerase regulation is another aspect under study in the laboratory.

Sonal Temburni
Research Assistant
Education: B.S. SUNY Stony Brook, NY, 2004; M.S. C.W. Post-Long Island University, NY, 2007
Research: B cell biology and CLL

Tara M. Schaaf 
Research Assistant
Education: B.A. SUNY New Paltz NY, 2007

University of Baroda, India
Degree: MS
1987
Field of Study: M.Sc. (Microbiology)

1. RN Damle, S Temburni, C Calissano, S Yancopoulos, T Banapour, C Sison, SL Allen, KR Rai and N Chiorazzi. CD38 expression labels an activated subset within chronic lymphocytic leukemia clones enriched in proliferating B cells. Blood (2007) 110(9): 3352-335
2. RN Damle, F Ghiotto, A Valetto, E Albesiano, F Fais, X-J Yan, CP Sison, SL Allen, J Kolitz, P Schulman, VP Vinciguerra, P Budde, J Frey, KR Rai, M Ferrarini and N Chiorazzi. “B-CLL cells express a surface membrane phenotype of activated, antigen-experienced B lymphocytes.” Blood: (2002) 99: 4087-4093.5.
3. RN Damle, T Wasil, F Fais, F Ghiotto, A Valetto, SL Allen, A Buchbinder, D Budman, K Dittmar, J Kolitz, SM Lichtman, P Schulman, VP Vinciguerra, KR Rai, M Ferrarini N Chiorazzi. “Immunoglobulin V gene mutation status and CD38 expression as novel prognostic indicators in Chronic lymphocytic leukemia.” Blood: (1999) 94: 1840-1847. [Special paper: FOCUS IN HEMATOLOGY]
4. F Morabito, RN Damle, S Deaglio, M Keating, M Ferrarini and N Chiorazzi. “The CD38 ectoenzyme family: advances in basic science and clinical practice.” Molecular Medicine. (2006) 12(11-12):342-4.
5. RN Damle, FM Batliwalla, F. Ghiotto, A Valetto, E Albesiano, S Allen, P Schulman, V Vinciguerra, K Rai, M Ferrarini, PK Gregersen and N Chiorazzi. “Telomere length and telomerase activity delineate distinctive replicative features of the B-CLL subgroups defined by immunoglobulin V gene mutations.” Blood: (2004) 103(2): 375-82. [PLENARY PAPER]

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