Epigenetic repolarization of T lymphocytes from chronic lymphocytic leukemia patients

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BlankEpigenetic repolarization of T lymphocytes from chronic lymphocytic

leukemia patients using 5-aza-2'-deoxycytidine.

JA Dubovsky, JJ Powers, Y Gao, LF Mariusso, EM Sotomayor, and JA Pinilla-Ibarz

Leuk Res, March 4, 2011; .

Department of Experimental Therapeutics at H. Lee Moffitt Cancer Center, Tampa,

FL, USA; Department of Malignant Hematology at H. Lee Moffitt Cancer Center,

Tampa, FL, USA.

T cell immune dysfunction has an important role in the profound immunosupression

that characterizes chronic lymphocytic leukemia (CLL). Improper polarization of

T cells has been proposed as one of the mechanism involved. Mounting data

implicates chromatin regulation, namely promoter methylation, in the plasticity

of naive human T cells. Recent in vitro evidence indicates that this plasticity

may be phenotypically altered by using methylation inhibitors which are approved

for clinical use in certain types of cancer. These results beg the question: can

the ineffective polarization of T lymphocytes in the context of CLL be

effectively modulated using methylation inhibitors in a sustainable therapeutic

fashion? To answer this question our laboratory has studied the effects of

5-aza-2'-deoxycytidine (5A2) in helper and cytotoxic T lymphocytes from healthy

donors and CLL patients in well characterized molecular and epigenetic signaling

pathways involved in effective polarization. Moreover, we sought to investigate

the consequences of methylation inhibitor treatment on lymphocyte survival,

activation intensity, and na?ve cell polarization. Our data indicates that 5A2

treatment can repolarize Th2 cells to effectively secrete interferon gamma,

signal via T-bet, and achieve demethylation of critical Th1 specific promoters.

Moreover, we demonstrate that 5A2 can force Th1 polarization of naive T cells

despite a strong IL-4 stimuli and a lack of IL-12. In conclusion our data seeks

to define a modality in which improper or ineffective T cell polarization can be

altered by 5AZA and could be incorporated in future therapeutic interventions.

PMID: 21377729