TY - JOUR
T1 - Novel role of prostate apoptosis response-4 tumor suppressor in B-cell chronic lymphocytic leukemia
AU - McKenna, Mary K.
AU - Noothi, Sunil K.
AU - Alhakeem, Sara S.
AU - Oben, Karine Z.
AU - Greene, Joseph T.
AU - Mani, Rajeswaran
AU - Perry, Kathryn L.
AU - Collard, James P.
AU - Rivas, Jacqueline R.
AU - Hildebrandt, Gerhard C.
AU - Fleischman, Roger A.
AU - Durbin, Eric B.
AU - Byrd, John C.
AU - Wang, Chi
AU - Muthusamy, Natarajan
AU - Rangnekar, Vivek M.
AU - Bondada, Subbarao
N1 - Publisher Copyright:
© 2018 by The American Society of Hematology
PY - 2018/6/28
Y1 - 2018/6/28
N2 - Prostate apoptosis response-4 (Par-4), a proapoptotic tumor suppressor protein, is downregulated in many cancers including renal cell carcinoma, glioblastoma, endometrial, and breast cancer. Par-4 induces apoptosis selectively in various types of cancer cells but not normal cells. We found that chronic lymphocytic leukemia (CLL) cells from human patients and from Em-Tcl1 mice constitutively express Par-4 in greater amounts than normal B-1 or B-2 cells. Interestingly, knockdown of Par-4 in human CLL-derived Mec-1 cells results in a robust increase in p21/WAF1 expression and decreased growth due to delayed G1-to-S cell-cycle transition. Lack of Par-4 also increased the expression of p21 and delayed CLL growth in Em-Tcl1 mice. Par-4 expression in CLL cells required constitutively active B-cell receptor (BCR) signaling, as inhibition of BCR signaling with US Food and Drug Administration (FDA)–approved drugs caused a decrease in Par-4 messenger RNA and protein, and an increase in apoptosis. In particular, activities of Lyn, a Src family kinase, spleen tyrosine kinase, and Bruton tyrosine kinase are required for Par-4 expression in CLL cells, suggesting a novel regulation of Par-4 through BCR signaling. Together, these results suggest that Par-4 may play a novel progrowth rather than proapoptotic role in CLL and could be targeted to enhance the therapeutic effects of BCR-signaling inhibitors.
AB - Prostate apoptosis response-4 (Par-4), a proapoptotic tumor suppressor protein, is downregulated in many cancers including renal cell carcinoma, glioblastoma, endometrial, and breast cancer. Par-4 induces apoptosis selectively in various types of cancer cells but not normal cells. We found that chronic lymphocytic leukemia (CLL) cells from human patients and from Em-Tcl1 mice constitutively express Par-4 in greater amounts than normal B-1 or B-2 cells. Interestingly, knockdown of Par-4 in human CLL-derived Mec-1 cells results in a robust increase in p21/WAF1 expression and decreased growth due to delayed G1-to-S cell-cycle transition. Lack of Par-4 also increased the expression of p21 and delayed CLL growth in Em-Tcl1 mice. Par-4 expression in CLL cells required constitutively active B-cell receptor (BCR) signaling, as inhibition of BCR signaling with US Food and Drug Administration (FDA)–approved drugs caused a decrease in Par-4 messenger RNA and protein, and an increase in apoptosis. In particular, activities of Lyn, a Src family kinase, spleen tyrosine kinase, and Bruton tyrosine kinase are required for Par-4 expression in CLL cells, suggesting a novel regulation of Par-4 through BCR signaling. Together, these results suggest that Par-4 may play a novel progrowth rather than proapoptotic role in CLL and could be targeted to enhance the therapeutic effects of BCR-signaling inhibitors.
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U2 - 10.1182/blood-2017-10-813931
DO - 10.1182/blood-2017-10-813931
M3 - Article
C2 - 29695515
AN - SCOPUS:85049123796
SN - 0006-4971
VL - 131
SP - 2943
EP - 2954
JO - Blood
JF - Blood
IS - 26
ER -
