PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis

Kallesh D. Jayappa; Brian Tran; Vicki L. Gordon; Christopher Morris; Shekhar Saha; Caroline C. Farrington; Caitlin M. O'Connor; Kaitlin P. Zawacki; Krista M. Isaac; Mark Kester; Timothy P. Bender; Michael E. Williams; Craig A. Portell; Michael J. Weber; Goutham Narla

doi:10.1172/JCI155938

PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis

Kallesh D. Jayappa, Brian Tran, Vicki L. Gordon, Christopher Morris, Shekhar Saha, Caroline C. Farrington, Caitlin M. O'Connor, Kaitlin P. Zawacki, Krista M. Isaac, Mark Kester, Timothy P. Bender, Michael E. Williams, Craig A. Portell, Michael J. Weber, Goutham Narla

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9 Scopus citations

Abstract

Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here, we demonstrated that multidrug-resistant CLL cells in vivo exhibited apoptosis restriction at a pre-mitochondrial level due to insufficient activation of the Bax and Bak (Bax/Bak) proteins. Coimmunoprecipitation analyses with selective BH domain antagonists revealed that the pleiotropic proapoptotic protein (Bim) was prevented from activating Bax/Bak by "switching"interactions to other upregulated antiapoptotic proteins (Mcl-1, Bcl-xL, Bcl-2). Hence, treatments that bypass Bax/Bak restriction are required to deplete these resistant cells in patients. Protein phosphatase 2A (PP2A) contributes to oncogenesis and treatment resistance. We observed that small-molecule activator of PP2A (SMAP) induced cytotoxicity in multiple cancer cell lines and CLL samples, including multidrug-resistant leukemia and lymphoma cells. The SMAP (DT-061) activated apoptosis in multidrug-resistant CLL cells through induction of mitochondrial permeability transition pores, independent of Bax/Bak. DT-061 inhibited the growth of wild-type and Bax/Bak doubleknockout, multidrug-resistant CLL cells in a xenograft mouse model. Collectively, we discovered multidrug-resistant CLL cells in patients and validated a pharmacologically tractable pathway to deplete this reservoir.

Original language	English
Article number	e155938
Journal	Journal of Clinical Investigation
Volume	133
Issue number	13
DOIs	https://doi.org/10.1172/JCI155938
State	Published - 3 Jul 2023
Externally published	Yes

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Jayappa, K. D., Tran, B., Gordon, V. L., Morris, C., Saha, S., Farrington, C. C., O'Connor, C. M., Zawacki, K. P., Isaac, K. M., Kester, M., Bender, T. P., Williams, M. E., Portell, C. A., Weber, M. J., & Narla, G. (2023). PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis. Journal of Clinical Investigation, 133(13), Article e155938. https://doi.org/10.1172/JCI155938

@article{a95044482a7240cb82fd1a81c25823c0,

title = "PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis",

abstract = "Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here, we demonstrated that multidrug-resistant CLL cells in vivo exhibited apoptosis restriction at a pre-mitochondrial level due to insufficient activation of the Bax and Bak (Bax/Bak) proteins. Coimmunoprecipitation analyses with selective BH domain antagonists revealed that the pleiotropic proapoptotic protein (Bim) was prevented from activating Bax/Bak by {"}switching{"}interactions to other upregulated antiapoptotic proteins (Mcl-1, Bcl-xL, Bcl-2). Hence, treatments that bypass Bax/Bak restriction are required to deplete these resistant cells in patients. Protein phosphatase 2A (PP2A) contributes to oncogenesis and treatment resistance. We observed that small-molecule activator of PP2A (SMAP) induced cytotoxicity in multiple cancer cell lines and CLL samples, including multidrug-resistant leukemia and lymphoma cells. The SMAP (DT-061) activated apoptosis in multidrug-resistant CLL cells through induction of mitochondrial permeability transition pores, independent of Bax/Bak. DT-061 inhibited the growth of wild-type and Bax/Bak doubleknockout, multidrug-resistant CLL cells in a xenograft mouse model. Collectively, we discovered multidrug-resistant CLL cells in patients and validated a pharmacologically tractable pathway to deplete this reservoir.",

author = "Jayappa, {Kallesh D.} and Brian Tran and Gordon, {Vicki L.} and Christopher Morris and Shekhar Saha and Farrington, {Caroline C.} and O'Connor, {Caitlin M.} and Zawacki, {Kaitlin P.} and Isaac, {Krista M.} and Mark Kester and Bender, {Timothy P.} and Williams, {Michael E.} and Portell, {Craig A.} and Weber, {Michael J.} and Goutham Narla",

note = "Publisher Copyright: {\textcopyright} 2023, Jayappa et al.",

year = "2023",

month = jul,

day = "3",

doi = "10.1172/JCI155938",

language = "English",

volume = "133",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

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Jayappa, KD, Tran, B, Gordon, VL, Morris, C, Saha, S, Farrington, CC, O'Connor, CM, Zawacki, KP, Isaac, KM, Kester, M, Bender, TP, Williams, ME, Portell, CA, Weber, MJ & Narla, G 2023, 'PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis', Journal of Clinical Investigation, vol. 133, no. 13, e155938. https://doi.org/10.1172/JCI155938

TY - JOUR

T1 - PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis

AU - Jayappa, Kallesh D.

AU - Tran, Brian

AU - Gordon, Vicki L.

AU - Morris, Christopher

AU - Saha, Shekhar

AU - Farrington, Caroline C.

AU - O'Connor, Caitlin M.

AU - Zawacki, Kaitlin P.

AU - Isaac, Krista M.

AU - Kester, Mark

AU - Bender, Timothy P.

AU - Williams, Michael E.

AU - Portell, Craig A.

AU - Weber, Michael J.

AU - Narla, Goutham

PY - 2023/7/3

Y1 - 2023/7/3

N2 - Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here, we demonstrated that multidrug-resistant CLL cells in vivo exhibited apoptosis restriction at a pre-mitochondrial level due to insufficient activation of the Bax and Bak (Bax/Bak) proteins. Coimmunoprecipitation analyses with selective BH domain antagonists revealed that the pleiotropic proapoptotic protein (Bim) was prevented from activating Bax/Bak by "switching"interactions to other upregulated antiapoptotic proteins (Mcl-1, Bcl-xL, Bcl-2). Hence, treatments that bypass Bax/Bak restriction are required to deplete these resistant cells in patients. Protein phosphatase 2A (PP2A) contributes to oncogenesis and treatment resistance. We observed that small-molecule activator of PP2A (SMAP) induced cytotoxicity in multiple cancer cell lines and CLL samples, including multidrug-resistant leukemia and lymphoma cells. The SMAP (DT-061) activated apoptosis in multidrug-resistant CLL cells through induction of mitochondrial permeability transition pores, independent of Bax/Bak. DT-061 inhibited the growth of wild-type and Bax/Bak doubleknockout, multidrug-resistant CLL cells in a xenograft mouse model. Collectively, we discovered multidrug-resistant CLL cells in patients and validated a pharmacologically tractable pathway to deplete this reservoir.

AB - Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here, we demonstrated that multidrug-resistant CLL cells in vivo exhibited apoptosis restriction at a pre-mitochondrial level due to insufficient activation of the Bax and Bak (Bax/Bak) proteins. Coimmunoprecipitation analyses with selective BH domain antagonists revealed that the pleiotropic proapoptotic protein (Bim) was prevented from activating Bax/Bak by "switching"interactions to other upregulated antiapoptotic proteins (Mcl-1, Bcl-xL, Bcl-2). Hence, treatments that bypass Bax/Bak restriction are required to deplete these resistant cells in patients. Protein phosphatase 2A (PP2A) contributes to oncogenesis and treatment resistance. We observed that small-molecule activator of PP2A (SMAP) induced cytotoxicity in multiple cancer cell lines and CLL samples, including multidrug-resistant leukemia and lymphoma cells. The SMAP (DT-061) activated apoptosis in multidrug-resistant CLL cells through induction of mitochondrial permeability transition pores, independent of Bax/Bak. DT-061 inhibited the growth of wild-type and Bax/Bak doubleknockout, multidrug-resistant CLL cells in a xenograft mouse model. Collectively, we discovered multidrug-resistant CLL cells in patients and validated a pharmacologically tractable pathway to deplete this reservoir.

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U2 - 10.1172/JCI155938

DO - 10.1172/JCI155938

M3 - Article

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AN - SCOPUS:85164211444

SN - 0021-9738

VL - 133

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 13

M1 - e155938

ER -

PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis

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