- Email: [email protected]
Venetoclax in Lymphoid Malignancies: New Insights, More to Learn
Cancer Cell
Previews Venetoclax in Lymphoid Malignancies: New Insights, More to Learn Rachel Thijssen1 and Andrew W. Roberts1,2,3,4,* 1The
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, 305 Grattan Street, Melbourne, VIC 3000, Australia 3Department of Medical Biology and Centre for Cancer Research, University of Melbourne, Melbourne, VIC 3000, Australia 4Victorian Comprehensive Cancer Centre, 305 Grattan Street, Melbourne, VIC 3000, Australia *Correspondence: [email protected] https://doi.org/10.1016/j.ccell.2019.09.008 2Clinical
In this issue of Cancer Cell, Guie`za et al. describe that overexpression of the pro-survival protein MCL1 and cellular energy metabolic reprogramming can contribute to resistance to the BCL2 inhibitor venetoclax in patients with chronic lymphocytic leukemia. This adds a new dimension to understanding of secondary clinical resistance to venetoclax. Venetoclax is the first member of a new class of anti-cancer drugs, termed BH3 mimetics, to enter routine clinical practice as an approved drug. BH3 mimetics have significant potential for treating a wide range of cancers, as they directly bind prosurvival proteins and trigger apoptosis. In chronic lymphocytic leukemia (CLL), BCL2 is universally highly expressed, enabling the leukemic cells to survive inappropriately and accumulate. Venetoclax is a potent and selective inhibitor of BCL2. As monotherapy and in combination with anti-CD20 monoclonal antibodies, it has proven to be effective for treating patients with CLL and is now a standard of care option for CLL in many countries. It achieves high rates of durable complete responses in this disease. Nevertheless, despite ongoing therapy, recurrence is observed over months and years (Roberts et al., 2019). Such secondary resistance is also observed in other cancers where venetoclax has demonstrated clinical activity in phase 1 and 2 trials, including acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM). Therefore, the authors sought to identify drivers of resistance in the setting of lymphoid malignancies by performing unbiased loss- and gain-of-function screens in a venetoclax sensitive NHL cell line (Guie`za et al., 2019). This study found loss of the pro-apoptotic genes PMAIP1 and BAX as top hits, similar to recent findings in AML cell lines (Nechiporuk et al., 2019). Genes that regulate lymphoid development (OTUD5, IKZF5, NFKB1A, ID3, UB35, NF1A, and EP300) were also
identified as hits. Initial validation included testing single gene knockouts and overexpression of the top candidate genes in isogenic cell lines in cytotoxicity assays with venetoclax. These generally only showed an 2-fold reduction in venetoclax sensitivity. This is a surprisingly small fold difference, given that fold changes in the in vitro sensitivity of CLL cells from patients before and at progression on venetoclax therapy have been reported to be greater, e.g., 20- to >100-fold (Blombery et al., 2019a). Nevertheless, a venetoclax-dependent in vitro growth advantage over time was demonstrated, indicating that each of these hits can enhance resistance to venetoclax. The authors then focused particular attention on two genetic aberrations where evidence for a role converged. One of the top candidate drivers of venetoclax resistance in the gain-of-function screen was overexpression of MCL1. MCL1 was also the only significant hit in a second mass spectrometry-based proteomics screen comparing a venetoclaxresistant cell line generated through serial passage in ever-increasing concentrations of venetoclax and its parental control. Like its close relative BCL2, MCL1 promotes cell survival and is overexpressed in many types of cancer. Inhibitors against MCL1 are being developed, and Guie`za and colleagues went on to demonstrate that pharmacological inhibition of MCL1 restored venetoclax sensitivity in resistant cell lines. Guie`za and colleagues also reported that multiple members of ‘‘metabolic stress’’ pathway play a role in venetoclax
resistance. In the genomic screen, cells that were enriched with genes of the AMPK pathway, including ADIPOQ, PRKAR2B, and PRKAA2, and of mitochondrial energy metabolism (SLC25A3) survive venetoclax treatment. In a complementary approach, the authors performed RNA sequencing in venetoclaxresistant cell lines and their sensitive counterparts and found that the top negatively regulated pathways were related to metabolism. To confirm that metabolic reprogramming plays a role in the resistance to venetoclax, mitochondrial respiration of the cell lines was evaluated. The resistant cell lines demonstrated higher rates of maximal oxygen consumption, higher steady-state levels of reactive oxygen species, and higher mitochondrial membrane potential than parental lines. To address whether venetoclax directly affects cellular energy metabolism, the authors measured oxygen consumption following acute venetoclax exposure and found a decrease in OXPHOS. In a cell line where the apoptosis effector proteins BAX and BAK are knocked out, no decrease in oxygen consumption was observed, indicating that the effect of venetoclax on OXPHOS requires mitochondria permeabilization by BAX and BAK, the process that commits cells to apoptosis. However, the effect appears not to require the late events of apoptosis, with reduced OXPHOS occurring despite blockade of caspase activity. Pharmacological inhibitors of the mitochondrial electron transport chain increased venetoclax sensitivity of DLBCL cell lines and also of primary treatment-naive CLL
Cancer Cell 36, October 14, 2019 ª 2019 Elsevier Inc. 341
Cancer Cell
Previews Metabolism
Apoptosis MCL1 amplification BCL2 G101V mutation
PRKAB2 amplification
BCLxL overexpression
BCL2 D103Y mutation
Cell cycle BTG1 mutation CDKN2A/B loss
? Figure 1. Cell-Intrinsic Mechanisms of Venetoclax Resistance Observed in Patients with CLL The graphic summarizes the cell-intrinsic aberrations implicated in resistance through analysis of patient samples in CLL. These have been observed in three general areas of cell function: the intrinsic pathway of apoptosis, energy metabolism, and cell-cycle regulation. Dark orange cells illustrate the novel insights provided by Guie`za et al. in this issue. Mid-orange cells indicate other mechanisms recently discovered (Blombery et al., 2019a; Herling et al., 2018; Tausch et al., 2019). Pale orange cells depict the as-yetunidentified mechanisms that explain resistance in cells not bearing any of these aberrations.
samples in vitro. Complementing these findings, targeting both BCL2 and mitochondrial electron transport chain delayed tumor formation in a DLBCL xenograft model. These data support analogous data in AML cells that OXPHOS can impact sensitivity to BCL2 inhibition (Jones et al., 2018; Lagadinou et al., 2013). While screens in preclinical models teach us how venetoclax resistance may occur, it is detailed observations in cells from patients whose disease progresses on venetoclax that reveal what does occur and what matters clinically. In this study, the authors performed wholeexome sequencing in paired samples from patients prior to venetoclax therapy and following early CLL progression. In line with previous studies (Blombery et al., 2019a; Herling et al., 2018), Guie`za and colleagues did not find unidirectional 342 Cancer Cell 36, October 14, 2019
selection of clones with the known CLL driver mutations such as TP53, ATM, or SF3B1 upon venetoclax relapse. However, the authors discovered a recurrence of amplification of 1q23 encompassing both MCL1 and PRKAB2, encoding an AMPK pathway component, in 4/6 cases with progressive disease. In support of the functional relevance of these findings, increased expression of MCL1 was observed in post-venetoclax tissue samples from 6/9 patients, and increased AMPK signaling activation was found in post-venetoclax tissue samples from 4/9 patients. Amplification of 1q23 was only subclonal in most patient samples, suggesting that venetoclax resistance may not solely be driven by any one particular mutation or amplification but rather involves multiple complex changes. This study therefore contributes two further important pieces to the still-incom-
plete tapestry of adaptive changes observed in CLL cells that enable clinical resistance (Figure 1). Guie`za and colleagues’ identification of amplifications of MCL1 and PRKAB2 in CLL relapsing early during venetoclax therapy adds to previous discoveries of acquired loss of CDKN2A/B and mutation in BTG1 in patients whose CLL progressed within 2 years (Herling et al., 2018) and acquired mutations of BCL2 (G101V and D103Y) typically seen in late recurrence that emerges after many years on venetoclax (Blombery et al., 2019a; Tausch et al., 2019). The BCL2 G101V mutation conveys a 30-fold reduction in sensitivity to venetoclax by reducing the drug’s binding to BCL2, while not impairing BCL2’s ability to maintain cell survival (Blombery et al., 2019a). As now also observed for MCL1 amplification, BCL2 mutations are also commonly subclonal. The mutually exclusive occurrence of either BCL2 G101V or BCLxL overexpression has been observed in resistant CLL subclones in a single patient. Collectively, these studies bring us another step closer in understanding resistance to venetoclax in CLL. The field now awaits description of the important mechanisms of resistance in samples from patients with AML, MM, and NHL that progresses while on venetoclax. Based on the advances published this year, it seems reasonable to anticipate that some mechanisms will be shared across cell types, while others will be more cell context dependent. Very recently, case reports have indicated the emergence of BCL2 F104I in a patient with recurrent follicular lymphoma (Blombery et al., 2019b) and epigenetic upregulation of BCLxL in mantle cell lymphoma (Agarwal et al., 2019). Given that multiple avenues to venetoclax resistance are being revealed, a key focus of future research must be on whether combination therapy can close the door on these escape routes. ACKNOWLEDGMENTS R.T. is supported by a Fellowship for the Leukemia and Lymphoma Society (5467-18), and A.W.R is supported by a Practitioner Fellowship of the National Health and Medical Research Council of Australia (1079560). DECLARATION OF INTERESTS R.T. and A.W.R. are employees of the Walter and Eliza Hall Institute (WEHI), which receives
Cancer Cell
Previews milestone and royalty payments related to venetoclax. A.W.R. receives payments from WEHI related to venetoclax and has previously received research funding from AbbVie and Janssen. REFERENCES Agarwal, R., Chan, Y.C., Tam, C.S., Hunter, T., Vassiliadis, D., Teh, C.E., Thijssen, R., Yeh, P., Wong, S.Q., Ftouni, S., et al. (2019). Dynamic molecular monitoring reveals that SWI-SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma. Nat. Med. 25, 119–129. Blombery, P., Anderson, M.A., Gong, J.N., Thijssen, R., Birkinshaw, R.W., Thompson, E.R., Teh, C.E., Nguyen, T., Xu, Z., Flensburg, C., et al. (2019a). Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to Venetoclax in patients with progressive chronic lymphocytic leukemia. Cancer Discov. 9, 342–353. Blombery, P., Birkinshaw, R.W., Nguyen, T., Gong, J.N., Thompson, E.R., Xu, Z., Westerman, D.A., Czabotar, P.E., Dickinson, M., Huang, D.C.S., et al. (2019b). Characterization of a novel veneto-
clax resistance mutation (BCL2 Phe104Ile) observed in follicular lymphoma. Br. J. Haematol. 186, e188–e191. Guie`ze, R., Liu, V.M., Rosebrock, D., Jourdain, A.A., Herna´ndez-Sa´nchez, M., Martinez Zurita, A., Sun, J., Ten Hacken, E., Baranowski, K., Thompson, P.A., et al. (2019). Mitochondrial reprogramming underlies resistance to BCL-2 inhibition in lymphoid malignancies. Cancer Cell 36, this issue, 369–384. Herling, C.D., Abedpour, N., Weiss, J., Schmitt, A., Jachimowicz, R.D., Merkel, O., Cartolano, M., Oberbeck, S., Mayer, P., Berg, V., et al. (2018). Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia. Nat. Commun. 9, 727. Jones, C.L., Stevens, B.M., D’Alessandro, A., Reisz, J.A., Culp-Hill, R., Nemkov, T., Pei, S., Khan, N., Adane, B., Ye, H., et al. (2018). Inhibition of amino acid metabolism selectively targets human leukemia stem cells. Cancer Cell 34, 724–740.
Lagadinou, E.D., Sach, A., Callahan, K., Rossi, R.M., Neering, S.J., Minhajuddin, M., Ashton, J.M., Pei, S., Grose, V., O’Dwyer, K.M., et al. (2013). BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell 12, 329–341. Nechiporuk, T., Kurtz, S.E., Nikolova, O., Liu, T., Jones, C.L., D’Alessandro, A., Culp-Hill, R., d’Almeida, A., Joshi, S.K., Rosenberg, M., et al. (2019). The TP53 apoptotic network is a primary mediator of resistance to BCL2 inhibition in AML cells. Cancer Discov. 9, 910–925. Roberts, A.W., Ma, S., Kipps, T.J., Coutre, S.E., Davids, M.S., Eichhorst, B., Hallek, M., Byrd, J.C., Humphrey, K., Zhou, L., et al. (2019). Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables. Blood 134, 111–122. Tausch, E., Close, W., Dolnik, A., Bloehdorn, J., Chyla, B., Bullinger, L., Do¨hner, H., Mertens, D., and Stilgenbauer, S. (2019). Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia. Haematologica 104, e434–e437.
PRC2 Plays Red Light, Green Light with MHC-I and CD8+ T Cells Johnathan R. Whetstine1,* 1Fox Chase Cancer Center, Institute for Cancer Research, Cancer Epigenetics Program, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA *Correspondence: [email protected] https://doi.org/10.1016/j.ccell.2019.09.010
In this issue of Cancer Cell, Burr et al. report that PRC2 plays a conserved role in silencing antigen presentation and processing genes and, in turn, CD8+ T cell activation. Furthermore, PRC2-targeted therapeutics overcome gene silencing and promote tumor clearance by cytotoxic T cells. The inability of the immune system to target tumors is a major clinical problem (Garrido et al., 2016; Leone et al., 2013). A common route for tumor cells to achieve invisibility from cytotoxic T cells is the suppression of antigen presentation on their surface (Garrido et al., 2016; Leone et al., 2013). The major histocompatibility complex (MHC) presents peptides to the immune cells. MHC class I (MHC-I) molecules primarily present the peptides derived from the ubiquitin-proteosomal degradation, whereas MHC-II molecules present lysosomal-derived peptides (Leone et al., 2013). The process of antigen presentation is facilitated by the antigen-processing and -presenting machinery (APM), which includes peptide transporters, endoplasmic
reticulum chaperones, and the Golgi apparatus (Leone et al., 2013). Tumors have acquired various ways to suppress MHC and APM molecules in order to evade immune surveillance and immune therapy (Patel et al., 2017). Therefore, there is an urgent need to better understand pathways that control expression of antigen presentation genes and lymphocyte activation in order to develop more-effective therapeutic options. Burr and colleagues (2019) conducted a genome-wide screen to identify genes modulating MHC-I and APM gene silencing. They observed a significant enrichment for the polycomb repressive complex 2 (PRC2) core components, EZH2 and EED, and an accessory protein,
MTF2/PCL2 (Figure 1). PRC2 mediates the majority of histone 3 lysine 27 trimethylation (H3K27me3), leading to repression of genes. EZH2 is the main H3K27me3 methyltransferase in the PRC2 complex, whereas EZH1 has reduced H3K27 methylation activity (Schuettengruber et al., 2017). There are currently two main PRC2 complexes (PRC2.1 and PRC2.2) that are distinguished by their accessory proteins (Schuettengruber et al., 2017; van Mierlo et al., 2019). Since the accessory protein MTF2/PCL2 was enriched in the HLA expression screen, future studies should interrogate whether the PRC2.1 subcomplex specifically regulates MHC-I and APM silencing.
Cancer Cell 36, October 14, 2019 ª 2019 Elsevier Inc. 343
Previews Venetoclax in Lymphoid Malignancies: New Insights, More to Learn Rachel Thijssen1 and Andrew W. Roberts1,2,3,4,* 1The
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, 305 Grattan Street, Melbourne, VIC 3000, Australia 3Department of Medical Biology and Centre for Cancer Research, University of Melbourne, Melbourne, VIC 3000, Australia 4Victorian Comprehensive Cancer Centre, 305 Grattan Street, Melbourne, VIC 3000, Australia *Correspondence: [email protected] https://doi.org/10.1016/j.ccell.2019.09.008 2Clinical
In this issue of Cancer Cell, Guie`za et al. describe that overexpression of the pro-survival protein MCL1 and cellular energy metabolic reprogramming can contribute to resistance to the BCL2 inhibitor venetoclax in patients with chronic lymphocytic leukemia. This adds a new dimension to understanding of secondary clinical resistance to venetoclax. Venetoclax is the first member of a new class of anti-cancer drugs, termed BH3 mimetics, to enter routine clinical practice as an approved drug. BH3 mimetics have significant potential for treating a wide range of cancers, as they directly bind prosurvival proteins and trigger apoptosis. In chronic lymphocytic leukemia (CLL), BCL2 is universally highly expressed, enabling the leukemic cells to survive inappropriately and accumulate. Venetoclax is a potent and selective inhibitor of BCL2. As monotherapy and in combination with anti-CD20 monoclonal antibodies, it has proven to be effective for treating patients with CLL and is now a standard of care option for CLL in many countries. It achieves high rates of durable complete responses in this disease. Nevertheless, despite ongoing therapy, recurrence is observed over months and years (Roberts et al., 2019). Such secondary resistance is also observed in other cancers where venetoclax has demonstrated clinical activity in phase 1 and 2 trials, including acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM). Therefore, the authors sought to identify drivers of resistance in the setting of lymphoid malignancies by performing unbiased loss- and gain-of-function screens in a venetoclax sensitive NHL cell line (Guie`za et al., 2019). This study found loss of the pro-apoptotic genes PMAIP1 and BAX as top hits, similar to recent findings in AML cell lines (Nechiporuk et al., 2019). Genes that regulate lymphoid development (OTUD5, IKZF5, NFKB1A, ID3, UB35, NF1A, and EP300) were also
identified as hits. Initial validation included testing single gene knockouts and overexpression of the top candidate genes in isogenic cell lines in cytotoxicity assays with venetoclax. These generally only showed an 2-fold reduction in venetoclax sensitivity. This is a surprisingly small fold difference, given that fold changes in the in vitro sensitivity of CLL cells from patients before and at progression on venetoclax therapy have been reported to be greater, e.g., 20- to >100-fold (Blombery et al., 2019a). Nevertheless, a venetoclax-dependent in vitro growth advantage over time was demonstrated, indicating that each of these hits can enhance resistance to venetoclax. The authors then focused particular attention on two genetic aberrations where evidence for a role converged. One of the top candidate drivers of venetoclax resistance in the gain-of-function screen was overexpression of MCL1. MCL1 was also the only significant hit in a second mass spectrometry-based proteomics screen comparing a venetoclaxresistant cell line generated through serial passage in ever-increasing concentrations of venetoclax and its parental control. Like its close relative BCL2, MCL1 promotes cell survival and is overexpressed in many types of cancer. Inhibitors against MCL1 are being developed, and Guie`za and colleagues went on to demonstrate that pharmacological inhibition of MCL1 restored venetoclax sensitivity in resistant cell lines. Guie`za and colleagues also reported that multiple members of ‘‘metabolic stress’’ pathway play a role in venetoclax
resistance. In the genomic screen, cells that were enriched with genes of the AMPK pathway, including ADIPOQ, PRKAR2B, and PRKAA2, and of mitochondrial energy metabolism (SLC25A3) survive venetoclax treatment. In a complementary approach, the authors performed RNA sequencing in venetoclaxresistant cell lines and their sensitive counterparts and found that the top negatively regulated pathways were related to metabolism. To confirm that metabolic reprogramming plays a role in the resistance to venetoclax, mitochondrial respiration of the cell lines was evaluated. The resistant cell lines demonstrated higher rates of maximal oxygen consumption, higher steady-state levels of reactive oxygen species, and higher mitochondrial membrane potential than parental lines. To address whether venetoclax directly affects cellular energy metabolism, the authors measured oxygen consumption following acute venetoclax exposure and found a decrease in OXPHOS. In a cell line where the apoptosis effector proteins BAX and BAK are knocked out, no decrease in oxygen consumption was observed, indicating that the effect of venetoclax on OXPHOS requires mitochondria permeabilization by BAX and BAK, the process that commits cells to apoptosis. However, the effect appears not to require the late events of apoptosis, with reduced OXPHOS occurring despite blockade of caspase activity. Pharmacological inhibitors of the mitochondrial electron transport chain increased venetoclax sensitivity of DLBCL cell lines and also of primary treatment-naive CLL
Cancer Cell 36, October 14, 2019 ª 2019 Elsevier Inc. 341
Cancer Cell
Previews Metabolism
Apoptosis MCL1 amplification BCL2 G101V mutation
PRKAB2 amplification
BCLxL overexpression
BCL2 D103Y mutation
Cell cycle BTG1 mutation CDKN2A/B loss
? Figure 1. Cell-Intrinsic Mechanisms of Venetoclax Resistance Observed in Patients with CLL The graphic summarizes the cell-intrinsic aberrations implicated in resistance through analysis of patient samples in CLL. These have been observed in three general areas of cell function: the intrinsic pathway of apoptosis, energy metabolism, and cell-cycle regulation. Dark orange cells illustrate the novel insights provided by Guie`za et al. in this issue. Mid-orange cells indicate other mechanisms recently discovered (Blombery et al., 2019a; Herling et al., 2018; Tausch et al., 2019). Pale orange cells depict the as-yetunidentified mechanisms that explain resistance in cells not bearing any of these aberrations.
samples in vitro. Complementing these findings, targeting both BCL2 and mitochondrial electron transport chain delayed tumor formation in a DLBCL xenograft model. These data support analogous data in AML cells that OXPHOS can impact sensitivity to BCL2 inhibition (Jones et al., 2018; Lagadinou et al., 2013). While screens in preclinical models teach us how venetoclax resistance may occur, it is detailed observations in cells from patients whose disease progresses on venetoclax that reveal what does occur and what matters clinically. In this study, the authors performed wholeexome sequencing in paired samples from patients prior to venetoclax therapy and following early CLL progression. In line with previous studies (Blombery et al., 2019a; Herling et al., 2018), Guie`za and colleagues did not find unidirectional 342 Cancer Cell 36, October 14, 2019
selection of clones with the known CLL driver mutations such as TP53, ATM, or SF3B1 upon venetoclax relapse. However, the authors discovered a recurrence of amplification of 1q23 encompassing both MCL1 and PRKAB2, encoding an AMPK pathway component, in 4/6 cases with progressive disease. In support of the functional relevance of these findings, increased expression of MCL1 was observed in post-venetoclax tissue samples from 6/9 patients, and increased AMPK signaling activation was found in post-venetoclax tissue samples from 4/9 patients. Amplification of 1q23 was only subclonal in most patient samples, suggesting that venetoclax resistance may not solely be driven by any one particular mutation or amplification but rather involves multiple complex changes. This study therefore contributes two further important pieces to the still-incom-
plete tapestry of adaptive changes observed in CLL cells that enable clinical resistance (Figure 1). Guie`za and colleagues’ identification of amplifications of MCL1 and PRKAB2 in CLL relapsing early during venetoclax therapy adds to previous discoveries of acquired loss of CDKN2A/B and mutation in BTG1 in patients whose CLL progressed within 2 years (Herling et al., 2018) and acquired mutations of BCL2 (G101V and D103Y) typically seen in late recurrence that emerges after many years on venetoclax (Blombery et al., 2019a; Tausch et al., 2019). The BCL2 G101V mutation conveys a 30-fold reduction in sensitivity to venetoclax by reducing the drug’s binding to BCL2, while not impairing BCL2’s ability to maintain cell survival (Blombery et al., 2019a). As now also observed for MCL1 amplification, BCL2 mutations are also commonly subclonal. The mutually exclusive occurrence of either BCL2 G101V or BCLxL overexpression has been observed in resistant CLL subclones in a single patient. Collectively, these studies bring us another step closer in understanding resistance to venetoclax in CLL. The field now awaits description of the important mechanisms of resistance in samples from patients with AML, MM, and NHL that progresses while on venetoclax. Based on the advances published this year, it seems reasonable to anticipate that some mechanisms will be shared across cell types, while others will be more cell context dependent. Very recently, case reports have indicated the emergence of BCL2 F104I in a patient with recurrent follicular lymphoma (Blombery et al., 2019b) and epigenetic upregulation of BCLxL in mantle cell lymphoma (Agarwal et al., 2019). Given that multiple avenues to venetoclax resistance are being revealed, a key focus of future research must be on whether combination therapy can close the door on these escape routes. ACKNOWLEDGMENTS R.T. is supported by a Fellowship for the Leukemia and Lymphoma Society (5467-18), and A.W.R is supported by a Practitioner Fellowship of the National Health and Medical Research Council of Australia (1079560). DECLARATION OF INTERESTS R.T. and A.W.R. are employees of the Walter and Eliza Hall Institute (WEHI), which receives
Cancer Cell
Previews milestone and royalty payments related to venetoclax. A.W.R. receives payments from WEHI related to venetoclax and has previously received research funding from AbbVie and Janssen. REFERENCES Agarwal, R., Chan, Y.C., Tam, C.S., Hunter, T., Vassiliadis, D., Teh, C.E., Thijssen, R., Yeh, P., Wong, S.Q., Ftouni, S., et al. (2019). Dynamic molecular monitoring reveals that SWI-SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma. Nat. Med. 25, 119–129. Blombery, P., Anderson, M.A., Gong, J.N., Thijssen, R., Birkinshaw, R.W., Thompson, E.R., Teh, C.E., Nguyen, T., Xu, Z., Flensburg, C., et al. (2019a). Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to Venetoclax in patients with progressive chronic lymphocytic leukemia. Cancer Discov. 9, 342–353. Blombery, P., Birkinshaw, R.W., Nguyen, T., Gong, J.N., Thompson, E.R., Xu, Z., Westerman, D.A., Czabotar, P.E., Dickinson, M., Huang, D.C.S., et al. (2019b). Characterization of a novel veneto-
clax resistance mutation (BCL2 Phe104Ile) observed in follicular lymphoma. Br. J. Haematol. 186, e188–e191. Guie`ze, R., Liu, V.M., Rosebrock, D., Jourdain, A.A., Herna´ndez-Sa´nchez, M., Martinez Zurita, A., Sun, J., Ten Hacken, E., Baranowski, K., Thompson, P.A., et al. (2019). Mitochondrial reprogramming underlies resistance to BCL-2 inhibition in lymphoid malignancies. Cancer Cell 36, this issue, 369–384. Herling, C.D., Abedpour, N., Weiss, J., Schmitt, A., Jachimowicz, R.D., Merkel, O., Cartolano, M., Oberbeck, S., Mayer, P., Berg, V., et al. (2018). Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia. Nat. Commun. 9, 727. Jones, C.L., Stevens, B.M., D’Alessandro, A., Reisz, J.A., Culp-Hill, R., Nemkov, T., Pei, S., Khan, N., Adane, B., Ye, H., et al. (2018). Inhibition of amino acid metabolism selectively targets human leukemia stem cells. Cancer Cell 34, 724–740.
Lagadinou, E.D., Sach, A., Callahan, K., Rossi, R.M., Neering, S.J., Minhajuddin, M., Ashton, J.M., Pei, S., Grose, V., O’Dwyer, K.M., et al. (2013). BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell 12, 329–341. Nechiporuk, T., Kurtz, S.E., Nikolova, O., Liu, T., Jones, C.L., D’Alessandro, A., Culp-Hill, R., d’Almeida, A., Joshi, S.K., Rosenberg, M., et al. (2019). The TP53 apoptotic network is a primary mediator of resistance to BCL2 inhibition in AML cells. Cancer Discov. 9, 910–925. Roberts, A.W., Ma, S., Kipps, T.J., Coutre, S.E., Davids, M.S., Eichhorst, B., Hallek, M., Byrd, J.C., Humphrey, K., Zhou, L., et al. (2019). Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables. Blood 134, 111–122. Tausch, E., Close, W., Dolnik, A., Bloehdorn, J., Chyla, B., Bullinger, L., Do¨hner, H., Mertens, D., and Stilgenbauer, S. (2019). Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia. Haematologica 104, e434–e437.
PRC2 Plays Red Light, Green Light with MHC-I and CD8+ T Cells Johnathan R. Whetstine1,* 1Fox Chase Cancer Center, Institute for Cancer Research, Cancer Epigenetics Program, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA *Correspondence: [email protected] https://doi.org/10.1016/j.ccell.2019.09.010
In this issue of Cancer Cell, Burr et al. report that PRC2 plays a conserved role in silencing antigen presentation and processing genes and, in turn, CD8+ T cell activation. Furthermore, PRC2-targeted therapeutics overcome gene silencing and promote tumor clearance by cytotoxic T cells. The inability of the immune system to target tumors is a major clinical problem (Garrido et al., 2016; Leone et al., 2013). A common route for tumor cells to achieve invisibility from cytotoxic T cells is the suppression of antigen presentation on their surface (Garrido et al., 2016; Leone et al., 2013). The major histocompatibility complex (MHC) presents peptides to the immune cells. MHC class I (MHC-I) molecules primarily present the peptides derived from the ubiquitin-proteosomal degradation, whereas MHC-II molecules present lysosomal-derived peptides (Leone et al., 2013). The process of antigen presentation is facilitated by the antigen-processing and -presenting machinery (APM), which includes peptide transporters, endoplasmic
reticulum chaperones, and the Golgi apparatus (Leone et al., 2013). Tumors have acquired various ways to suppress MHC and APM molecules in order to evade immune surveillance and immune therapy (Patel et al., 2017). Therefore, there is an urgent need to better understand pathways that control expression of antigen presentation genes and lymphocyte activation in order to develop more-effective therapeutic options. Burr and colleagues (2019) conducted a genome-wide screen to identify genes modulating MHC-I and APM gene silencing. They observed a significant enrichment for the polycomb repressive complex 2 (PRC2) core components, EZH2 and EED, and an accessory protein,
MTF2/PCL2 (Figure 1). PRC2 mediates the majority of histone 3 lysine 27 trimethylation (H3K27me3), leading to repression of genes. EZH2 is the main H3K27me3 methyltransferase in the PRC2 complex, whereas EZH1 has reduced H3K27 methylation activity (Schuettengruber et al., 2017). There are currently two main PRC2 complexes (PRC2.1 and PRC2.2) that are distinguished by their accessory proteins (Schuettengruber et al., 2017; van Mierlo et al., 2019). Since the accessory protein MTF2/PCL2 was enriched in the HLA expression screen, future studies should interrogate whether the PRC2.1 subcomplex specifically regulates MHC-I and APM silencing.
Cancer Cell 36, October 14, 2019 ª 2019 Elsevier Inc. 343