Novel role of prostate apoptosis response-4 tumor suppressor in B-cell chronic lymphocytic leukemia

Mary K. McKenna; Sunil K. Noothi; Sara S. Alhakeem; Karine Z. Oben; Joseph T. Greene; Rajeswaran Mani; Kathryn L. Perry; James P. Collard; Jacqueline R. Rivas; Gerhard C. Hildebrandt; Roger A. Fleischman; Eric B. Durbin; John C. Byrd; Chi Wang; Natarajan Muthusamy; Vivek M. Rangnekar; Subbarao Bondada

doi:10.1182/blood-2017-10-813931

Novel role of prostate apoptosis response-4 tumor suppressor in B-cell chronic lymphocytic leukemia

Mary K. McKenna, Sunil K. Noothi, Sara S. Alhakeem, Karine Z. Oben, Joseph T. Greene, Rajeswaran Mani, Kathryn L. Perry, James P. Collard, Jacqueline R. Rivas, Gerhard C. Hildebrandt, Roger A. Fleischman, Eric B. Durbin, John C. Byrd, Chi Wang, Natarajan Muthusamy, Vivek M. Rangnekar, Subbarao Bondada

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	2943-2954
Number of pages	12
Journal	Blood
Volume	131
Issue number	26
DOIs	https://doi.org/10.1182/blood-2017-10-813931
State	Published - Jun 28 2018

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health, National Cancer Institute (CA 165469) (N.M., V.M.R., and S.B.). M.K.M. and J.R.R. were supported by National Institutes of Health, National Cancer Institute T32 grant CA165990. This research was supported by the Biospecimen Procurement and Translational Pathology shared resource facilities of the University of Kentucky Markey Cancer Center (P30 CA177558). The Flow Cytometry & Cell Sorting core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center, and a National Cancer Institute Center Core Support Grant (P30 CA177558) to the University of Kentucky Markey Cancer Center.

Funding Information:
A special thanks to Nikhil Hebbar for expertise and assistance in performing the Par-4 apoptosis assays. Another special thanks to the Markey Cancer Center Hematology-Oncology Clinic nurses for help in collecting patient samples. This work was supported by the National Institutes of Health, National Cancer Institute (CA 165469) (N.M., V.M.R., and S.B.). M.K.M. and J.R.R. were supported by National Institutes of Health, National Cancer Institute T32 grant CA165990. This research was supported by the Biospecimen Procurement and Translational Pathology shared resource facilities of the University of Kentucky Markey Cancer Center (P30 CA177558). The Flow Cytometry & Cell Sorting core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center, and a National Cancer Institute Center Core Support Grant (P30 CA177558) to the University of Kentucky Markey Cancer Center.

Publisher Copyright:
© 2018 by The American Society of Hematology

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1182/blood-2017-10-813931

Cite this

McKenna, M. K., Noothi, S. K., Alhakeem, S. S., Oben, K. Z., Greene, J. T., Mani, R., Perry, K. L., Collard, J. P., Rivas, J. R., Hildebrandt, G. C., Fleischman, R. A., Durbin, E. B., Byrd, J. C., Wang, C., Muthusamy, N., Rangnekar, V. M., & Bondada, S. (2018). Novel role of prostate apoptosis response-4 tumor suppressor in B-cell chronic lymphocytic leukemia. Blood, 131(26), 2943-2954. https://doi.org/10.1182/blood-2017-10-813931

@article{02969a21845644cca13fd1a6fa5bc90e,

title = "Novel role of prostate apoptosis response-4 tumor suppressor in B-cell chronic lymphocytic leukemia",

abstract = "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.",

author = "McKenna, {Mary K.} and Noothi, {Sunil K.} and Alhakeem, {Sara S.} and Oben, {Karine Z.} and Greene, {Joseph T.} and Rajeswaran Mani and Perry, {Kathryn L.} and Collard, {James P.} and Rivas, {Jacqueline R.} and Hildebrandt, {Gerhard C.} and Fleischman, {Roger A.} and Durbin, {Eric B.} and Byrd, {John C.} and Chi Wang and Natarajan Muthusamy and Rangnekar, {Vivek M.} and Subbarao Bondada",

note = "Funding Information: This work was supported by the National Institutes of Health, National Cancer Institute (CA 165469) (N.M., V.M.R., and S.B.). M.K.M. and J.R.R. were supported by National Institutes of Health, National Cancer Institute T32 grant CA165990. This research was supported by the Biospecimen Procurement and Translational Pathology shared resource facilities of the University of Kentucky Markey Cancer Center (P30 CA177558). The Flow Cytometry & Cell Sorting core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center, and a National Cancer Institute Center Core Support Grant (P30 CA177558) to the University of Kentucky Markey Cancer Center. Funding Information: A special thanks to Nikhil Hebbar for expertise and assistance in performing the Par-4 apoptosis assays. Another special thanks to the Markey Cancer Center Hematology-Oncology Clinic nurses for help in collecting patient samples. This work was supported by the National Institutes of Health, National Cancer Institute (CA 165469) (N.M., V.M.R., and S.B.). M.K.M. and J.R.R. were supported by National Institutes of Health, National Cancer Institute T32 grant CA165990. This research was supported by the Biospecimen Procurement and Translational Pathology shared resource facilities of the University of Kentucky Markey Cancer Center (P30 CA177558). The Flow Cytometry & Cell Sorting core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center, and a National Cancer Institute Center Core Support Grant (P30 CA177558) to the University of Kentucky Markey Cancer Center. Publisher Copyright: {\textcopyright} 2018 by The American Society of Hematology",

year = "2018",

month = jun,

day = "28",

doi = "10.1182/blood-2017-10-813931",

language = "English",

volume = "131",

pages = "2943--2954",

number = "26",

}

McKenna, MK, Noothi, SK, Alhakeem, SS, Oben, KZ, Greene, JT, Mani, R, Perry, KL, Collard, JP, Rivas, JR, Hildebrandt, GC, Fleischman, RA , Durbin, EB, Byrd, JC, Wang, C, Muthusamy, N, Rangnekar, VM & Bondada, S 2018, 'Novel role of prostate apoptosis response-4 tumor suppressor in B-cell chronic lymphocytic leukemia', Blood, vol. 131, no. 26, pp. 2943-2954. https://doi.org/10.1182/blood-2017-10-813931

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 - Funding Information: This work was supported by the National Institutes of Health, National Cancer Institute (CA 165469) (N.M., V.M.R., and S.B.). M.K.M. and J.R.R. were supported by National Institutes of Health, National Cancer Institute T32 grant CA165990. This research was supported by the Biospecimen Procurement and Translational Pathology shared resource facilities of the University of Kentucky Markey Cancer Center (P30 CA177558). The Flow Cytometry & Cell Sorting core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center, and a National Cancer Institute Center Core Support Grant (P30 CA177558) to the University of Kentucky Markey Cancer Center. Funding Information: A special thanks to Nikhil Hebbar for expertise and assistance in performing the Par-4 apoptosis assays. Another special thanks to the Markey Cancer Center Hematology-Oncology Clinic nurses for help in collecting patient samples. This work was supported by the National Institutes of Health, National Cancer Institute (CA 165469) (N.M., V.M.R., and S.B.). M.K.M. and J.R.R. were supported by National Institutes of Health, National Cancer Institute T32 grant CA165990. This research was supported by the Biospecimen Procurement and Translational Pathology shared resource facilities of the University of Kentucky Markey Cancer Center (P30 CA177558). The Flow Cytometry & Cell Sorting core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center, and a National Cancer Institute Center Core Support Grant (P30 CA177558) to the University of Kentucky Markey Cancer Center. 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.

UR - http://www.scopus.com/inward/record.url?scp=85049123796&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049123796&partnerID=8YFLogxK

U2 - 10.1182/blood-2017-10-813931

DO - 10.1182/blood-2017-10-813931

M3 - Article

C2 - 29695515

AN - SCOPUS:85049123796

VL - 131

SP - 2943

EP - 2954

IS - 26

ER -

Novel role of prostate apoptosis response-4 tumor suppressor in B-cell chronic lymphocytic leukemia

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this