- Email: [email protected]
Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: BIM Finally
Cancer Cell
Previews Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: BIM Finally Jessie A. Brown1 and Adolfo Ferrando1,2,3,4,* 1Institute
for Cancer Genetics, Columbia University, New York, NY 10032, USA of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA 3Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA 4Department of Systems Biology, Columbia University, New York, NY 10032, USA *Correspondence: [email protected] https://doi.org/10.1016/j.ccell.2018.11.011 2Department
Glucocorticoid resistance represents a major challenge in treating acute lymphoblastic leukemia. In this issue of Cancer Cell, Jing and colleagues show epigenetic deregulation of glucocorticoid-induced BIM activation in glucocorticoid-resistant leukemia cells, and restore glucocorticoid-receptor-induced BIM upregulation with DNA demethylating agents to effectively enhance glucocorticoid response. Acute lymphoblastic leukemia (ALL) is a highly aggressive hematologic malignancy resulting from the transformation of early lymphoid progenitors. Once associated with a dismal prognosis, ALL is now a highly curable tumor (Hunger and Mullighan, 2015). Glucocorticoids were the first drugs introduced in the treatment of ALL over 50 years ago and have remained at the core of the treatment of ALL and other lymphoid malignancies ever since (Inaba and Pui, 2010). The importance of glucocorticoid therapy in ALL is underlined by the strong association of primary glucocorticoid resistance with poor prognosis. Thus, poor response to glucocorticoid treatment with prednisone, defined as failure to show effective cytoreduction after 7 days of therapy, is strongly associated with increased risk of relapse, and in vitro resistance to glucocorticoids is associated with unfavorable prognosis (Inaba and Pui, 2010). In addition, secondary resistance to glucocorticoid therapy is highly prevalent in relapsed ALL and is considered a prominent factor contributing to therapeutic failure (Inaba and Pui, 2010). Glucocorticoid drugs, synthetic analogs of cortisol, signal primarily via interaction with the glucocorticoid receptor NR3C1, which functions as ligand-activated transcription factor. Glucocorticoid signaling is integral in the control of most physiological systems, inducing broad, diverse and pleiotropic responses. Adrenal release of cortisol induces responses as diverse as increased blood sugar levels, decreased inflammation, increased food intake and alert responses
in the brain, and reduced bone formation to name a few. Therapeutic use of glucocorticoids leverages in many cases their anti-inflammatory effects, but also many other aspects of cortisol function. In the treatment of ALL and other lymphoid tumors, corticoid therapy exploits the capacity of glucocorticoids to selectively induce apoptosis in lymphoid cells. Transcriptional responses to glucocorticoid receptor activation are tissue and context specific, and the selective proapoptotic response to glucocorticoid receptor signaling in lymphoid cells depends on their capacity to induce lymphoidrestricted transcriptional upregulation of BCL2L11, which encodes the proapoptotic BH3-only factor BIM (Wang et al., 2003). Numerous aspects of glucocorticoid receptor function and regulation have been implicated in glucocorticoid resistance. These include decreased receptor auto-upregulation downstream of NOTCH1 signaling (Real et al., 2009), impaired glucocorticoid receptor activity resulting from posttranslational modifications induced by AKT (Piovan et al., 2013), defective glucocorticoid-induced transcriptional response secondary to mutations in important NR3C1 coactivators such as CREBBP (Mullighan et al., 2011), and relapse-associated mutations in NR3C1 (Oshima et al., 2016). All these mechanisms converge in defective glucocorticoid-induced transcription and consequent upregulation of BIM expression or impaired BIM-induced cell death, as in the case of mTOR signaling-mediated upregulation of MCL1, an antiapoptotic BCL2 family factor strongly antago-
nistic of BIM function (Wei et al., 2006). However, despite much research, the transcriptional basis of glucocorticoidinduced BIM upregulation and the mechanisms of glucocorticoid resistance in ALL remain incompletely understood. Jing et al. now provide evidence of epigenetic deregulation of NR3C1induced BIM upregulation as a mediator of impaired glucocorticoid response in ALL (Jing et al., 2018) (Figure 1). Based on the premise that glucocorticoids induce apoptosis in lymphoid cells, but not in other tissues, the authors first proposed that glucocorticoid-induced cell death could be mediated by genes under control of lymphoid-specific regulatory elements selectively occupied and regulated by the glucocorticoid receptor in glucocorticoid sensitive lymphoblastic leukemia cells. By mapping DNaseI hypersensitivity regions in lymphoid tissues and a broad array of non-lymphoid cell types, they identify over 11,000 lymphoid-specific chromatin open regions, 10% of which were occupied by the glucocorticoid receptor in glucocorticoid-sensitive lymphoblasts following glucocorticoid treatment. To identify regulatory sites potentially deregulated in glucocorticoid-resistant ALL cells, they focused on glucocorticoid-receptoroccupied regions located in the vicinity of genes differentially modulated by glucocorticoid treatment in glucocorticoid-sensitive ALL cells compared with glucocorticoid-resistant leukemia lymphoblasts. These analyses yielded 462 glucocorticoid-bound lymphoid-specific open regions associated with 389 genes,
Cancer Cell 34, December 10, 2018 ª 2018 Elsevier Inc. 869
Cancer Cell
Previews
Figure 1. Epigenetic Control of the BCL2L11 IGR Enhancer Controls Glucocorticoid-Induced BIM Upregulation and Programmed Cell Death
In non-lymphoid tissues, the BCL2L11 locus shows an inactive chromatin configuration at IGR which precludes glucocorticoid receptor binding and glucocorticoid-induced transcriptional activation, while lymphoid cells show accessible chromatin at this site. Glucocorticoid-sensitive ALL lymphoblasts show low levels of IGR methylation, that responds to glucocorticoid receptor binding with increased H3K27 acetylation, CTCF binding and looping to the BCL2L11 promoter to drive transcriptional activation and BIM upregulation with consequent activation of glucocorticoid-induced cell death. In contrast, glucocorticoid resistance is associated with increased enhancer methylation, decreased IGR accessibility, impaired glucocorticoid receptor binding, and failure to induce H3K27 acetylation, CTCF binding, and enhancer-promoter chromatin looping. By restoring a glucocorticoid-sensitive chromatin configuration at the BCL2L11 IGR enhancer, DNA demethylating agents can reverse glucocorticoid resistance. TSS, transcription start site.
of which 198 were upregulated and 191 were downregulated by glucocorticoid treatment only in glucocorticoid-sensitive cells. Epigenetic characterization of the chromatin landscape at these sites showed blunted changes in H3K27 acetylation in resistant cells. Moreover, DNA methylation and ATAC-seq profiling identified 42 glucocorticoid receptor interacting lymphoid-specific chromatin open regions harboring features of inactive chromatin—increased DNA methylation and reduced chromatin accessibility—in glucocorticoid-resistant leukemia cells. Extended ATAC-seq analysis in a broader panel of glucocorticoid sensitive and resistant ALL xenograft samples showed largely concordant results in support of a potential general role for impaired glucocorticoid-induced regulation of chromatin accessibility at these sites in glucocorticoid resistance. Notably, one of the glucocorticoid-bound lymphoid-specific open regions deregulated in resistant lymphoblasts corresponds to an intronic enhancer at the BCL2L11 locus. Functional characterization of this intronic glucocorticoid receptor-binding region (IGR) showed glucocorticoid-induced NR3C1 binding, increased chromatin accessibility and histone acetylation, as 870 Cancer Cell 34, December 10, 2018
well as glucocorticoid-induced transcriptional activation in reporter assays. Distal enhancers interact with and control the activity of proximal promoters via long-range chromatin loops in association with cohesin complexes and the CCCTC-binding factor CTCF. Consistently, analysis of CTCF occupancy showed increased binding by CTCF at the BCL2L11 IGR enhancer in sensitive cells treated with glucocorticoids, which correlated with the establishment of readily detectable promoter-enhancer interactions in chromosome conformation capture (3C) assays. Most notably, glucocorticoid-resistant lymphoblasts showed loss of CTCF binding in basal conditions and upon glucocorticoid treatment, which correlated with abrogation of glucocorticoid-induced BCL2L11 promoterenhancer interaction and transcriptional upregulation. A direct mechanistic role for the IGR enhancer is supported by loss of glucocorticoid-induced BCL2L11 transcriptional activation and cell death in glucocorticoid-sensitive cells after a focal deletion of this regulatory element. Chromatin accessibility is established by the activity of pioneering transcription factors, which can interact with nucleosomal DNA and mediate the recruitment of chro-
matin remodeling complexes to generate nucleosome-free regions accessible to transcription factor binding. Although the specific mechanisms responsible for lymphoid-restricted chromatin accessibility and activity of the BCL2L11 IGR remain to be fully elucidated, PU.1, a transcription factor described to have pioneering activity, interacts with this regulatory site in glucocorticoid-sensitive ALL cells and shows decreased binding in resistant lymphoblasts. In addition, DNA methylation at the IGR was increased in a broad panel of glucocorticoid-resistant leukemia xenografts supporting a role for DNA methylation in setting an inactive chromatin configuration. Consistent with this hypothesis, treatment of glucocorticoid-resistant ALL cells with 5-azacitidine, a DNA demethylating agent, reversed DNA methylation at this site, enhanced glucocorticoid-induced BCL2L11 upregulation, and enhanced glucocorticoid response in vitro. Concordantly, treatment with decitabine, a clinical DNA demethylating drug, showed increased therapeutic activity in combination with glucocorticoid treatment in vivo. Although much remains to be learned about epigenetic mechanisms in glucocorticoid resistance, this study underscores a
Cancer Cell
Previews potential role for local epigenetic-mediated silencing of the BCL2L11 IGR and potentially other glucocorticoid-controlled regulatory sites in glucocorticoid resistance. Importantly DNA methylation can alter CTCF binding, potentially linking increased focal methylation at the IGR with impaired enhancer-promoter looping. In addition, changes in chromatin accessibility could also be linked with DNA methylation, and the role of pioneering factors at this site remains to be fully explored. PU.1 binds to the IGR, yet PU.1 is prominently expressed in myeloid cells where the BCL2L11 IGR adopts a closed inactive chromatin configuration. Finally, it will be important to analyze the role of epigenetic heterogeneity and Darwinian selection of epi-alleles as drivers of glucocorticoid resistance in relapsed ALL (Ferrando and Lo´pez-Otı´n, 2017) and the potential role of this proposed mechanism in the response and resistance to glucocorticoid therapy in other lymphoid tumors.
REFERENCES Ferrando, A.A., and Lo´pez-Otı´n, C. (2017). Clonal evolution in leukemia. Nat. Med. 23, 1135–1145. Hunger, S.P., and Mullighan, C.G. (2015). Acute lymphoblastic leukemia in children. N. Engl. J. Med. 373, 1541–1552. Inaba, H., and Pui, C.H. (2010). Glucocorticoid use in acute lymphoblastic leukaemia. Lancet Oncol. 11, 1096–1106. Jing, D., Huang, Y., Liu, X., Sia, K.C.S., Zhang, J.C., Tai, X., Wang, M., Toscan, C.E., McCalmont, H., Evans, K., et al. (2018). Lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in acute lymphoblastic leukemia. Cancer Cell 34, this issue, 906–921. Mullighan, C.G., Zhang, J., Kasper, L.H., Lerach, S., Payne-Turner, D., Phillips, L.A., Heatley, S.L., Holmfeldt, L., Collins-Underwood, J.R., Ma, J., et al. (2011). CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature 471, 235–239. Oshima, K., Khiabanian, H., da Silva-Almeida, A.C., Tzoneva, G., Abate, F., Ambesi-Impiombato, A., Sanchez-Martin, M., Carpenter, Z., Penson, A., Perez-Garcia, A., et al. (2016). Mutational landscape, clonal evolution patterns, and role of
RAS mutations in relapsed acute lymphoblastic leukemia. Proc. Natl. Acad. Sci. USA 113, 11306–11311. Piovan, E., Yu, J., Tosello, V., Herranz, D., AmbesiImpiombato, A., Da Silva, A.C., Sanchez-Martin, M., Perez-Garcia, A., Rigo, I., Castillo, M., et al. (2013). Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia. Cancer Cell 24, 766–776. Real, P.J., Tosello, V., Palomero, T., Castillo, M., Hernando, E., de Stanchina, E., Sulis, M.L., Barnes, K., Sawai, C., Homminga, I., et al. (2009). Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat. Med. 15, 50–58. Wang, Z., Malone, M.H., He, H., McColl, K.S., and Distelhorst, C.W. (2003). Microarray analysis uncovers the induction of the proapoptotic BH3only protein Bim in multiple models of glucocorticoid-induced apoptosis. J. Biol. Chem. 278, 23861–23867. Wei, G., Twomey, D., Lamb, J., Schlis, K., Agarwal, J., Stam, R.W., Opferman, J.T., Sallan, S.E., den Boer, M.L., Pieters, R., et al. (2006). Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. Cancer Cell 10, 331–342.
From Basic Knowledge to Effective Therapies Daniel B. Lipka,1,2 Pavlo Lutsik,1 and Christoph Plass1,3,* 1Division
of Cancer Epigenomics, German Cancer Research Center, Heidelberg, Germany of Hematology and Oncology, Medical Center, Otto-von-Guericke-University, Magdeburg, Germany 3The German Cancer Research Consortium *Correspondence: [email protected] https://doi.org/10.1016/j.ccell.2018.11.013 2Department
In this issue of Cancer Cell, Ott et al. use integrative analysis of histone ChIP-seq and ATAC-seq to describe enhancer-based regulatory circuits in chronic lymphocytic leukemia. This work identified and validated transcription factor PAX5 as main driver of an oncogenic circuitry, which can be disrupted by BET bromodomain inhibition. Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia and is characterized by slowly proliferating B lymphocytes, which at the molecular level show defects in apoptosis. The clinical course of CLL is variable with indolent cases on one end and highly aggressive cases on the other end of the spectrum. Markers for aggressive forms of CLL include unmutated immunoglobulin heavy-chain variable region loci (IGHV) and aberrant expression of 70-kD zeta-associated protein
(ZAP-70), whereas indolent CLL cases show mutated IGHV and absence of ZAP-70 expression (Crespo et al., 2003). CLL is an excellent model system for basic and translational cancer research due to easy accessibility of malignant cells, the possibility to purify the malignant clones to highest purity, the availability of large cohorts of wellcharacterized biobanked samples from national and international clinical trials, and the availability of mouse models, recapitulating both indolent and aggres-
sive forms of the malignancy. Consequently, CLL has always been at the forefront of cancer research where the latest technologies have been applied in order to characterize the molecular defects underlying CLL pathogenesis. Very often, the information gained in such basic cancer research efforts has been translated into the clinic, either in form of novel diagnostic or prognostic models, or it has been used for the development of novel therapeutic approaches. This path is highlighted in
Cancer Cell 34, December 10, 2018 ª 2018 Elsevier Inc. 871
Previews Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: BIM Finally Jessie A. Brown1 and Adolfo Ferrando1,2,3,4,* 1Institute
for Cancer Genetics, Columbia University, New York, NY 10032, USA of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA 3Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA 4Department of Systems Biology, Columbia University, New York, NY 10032, USA *Correspondence: [email protected] https://doi.org/10.1016/j.ccell.2018.11.011 2Department
Glucocorticoid resistance represents a major challenge in treating acute lymphoblastic leukemia. In this issue of Cancer Cell, Jing and colleagues show epigenetic deregulation of glucocorticoid-induced BIM activation in glucocorticoid-resistant leukemia cells, and restore glucocorticoid-receptor-induced BIM upregulation with DNA demethylating agents to effectively enhance glucocorticoid response. Acute lymphoblastic leukemia (ALL) is a highly aggressive hematologic malignancy resulting from the transformation of early lymphoid progenitors. Once associated with a dismal prognosis, ALL is now a highly curable tumor (Hunger and Mullighan, 2015). Glucocorticoids were the first drugs introduced in the treatment of ALL over 50 years ago and have remained at the core of the treatment of ALL and other lymphoid malignancies ever since (Inaba and Pui, 2010). The importance of glucocorticoid therapy in ALL is underlined by the strong association of primary glucocorticoid resistance with poor prognosis. Thus, poor response to glucocorticoid treatment with prednisone, defined as failure to show effective cytoreduction after 7 days of therapy, is strongly associated with increased risk of relapse, and in vitro resistance to glucocorticoids is associated with unfavorable prognosis (Inaba and Pui, 2010). In addition, secondary resistance to glucocorticoid therapy is highly prevalent in relapsed ALL and is considered a prominent factor contributing to therapeutic failure (Inaba and Pui, 2010). Glucocorticoid drugs, synthetic analogs of cortisol, signal primarily via interaction with the glucocorticoid receptor NR3C1, which functions as ligand-activated transcription factor. Glucocorticoid signaling is integral in the control of most physiological systems, inducing broad, diverse and pleiotropic responses. Adrenal release of cortisol induces responses as diverse as increased blood sugar levels, decreased inflammation, increased food intake and alert responses
in the brain, and reduced bone formation to name a few. Therapeutic use of glucocorticoids leverages in many cases their anti-inflammatory effects, but also many other aspects of cortisol function. In the treatment of ALL and other lymphoid tumors, corticoid therapy exploits the capacity of glucocorticoids to selectively induce apoptosis in lymphoid cells. Transcriptional responses to glucocorticoid receptor activation are tissue and context specific, and the selective proapoptotic response to glucocorticoid receptor signaling in lymphoid cells depends on their capacity to induce lymphoidrestricted transcriptional upregulation of BCL2L11, which encodes the proapoptotic BH3-only factor BIM (Wang et al., 2003). Numerous aspects of glucocorticoid receptor function and regulation have been implicated in glucocorticoid resistance. These include decreased receptor auto-upregulation downstream of NOTCH1 signaling (Real et al., 2009), impaired glucocorticoid receptor activity resulting from posttranslational modifications induced by AKT (Piovan et al., 2013), defective glucocorticoid-induced transcriptional response secondary to mutations in important NR3C1 coactivators such as CREBBP (Mullighan et al., 2011), and relapse-associated mutations in NR3C1 (Oshima et al., 2016). All these mechanisms converge in defective glucocorticoid-induced transcription and consequent upregulation of BIM expression or impaired BIM-induced cell death, as in the case of mTOR signaling-mediated upregulation of MCL1, an antiapoptotic BCL2 family factor strongly antago-
nistic of BIM function (Wei et al., 2006). However, despite much research, the transcriptional basis of glucocorticoidinduced BIM upregulation and the mechanisms of glucocorticoid resistance in ALL remain incompletely understood. Jing et al. now provide evidence of epigenetic deregulation of NR3C1induced BIM upregulation as a mediator of impaired glucocorticoid response in ALL (Jing et al., 2018) (Figure 1). Based on the premise that glucocorticoids induce apoptosis in lymphoid cells, but not in other tissues, the authors first proposed that glucocorticoid-induced cell death could be mediated by genes under control of lymphoid-specific regulatory elements selectively occupied and regulated by the glucocorticoid receptor in glucocorticoid sensitive lymphoblastic leukemia cells. By mapping DNaseI hypersensitivity regions in lymphoid tissues and a broad array of non-lymphoid cell types, they identify over 11,000 lymphoid-specific chromatin open regions, 10% of which were occupied by the glucocorticoid receptor in glucocorticoid-sensitive lymphoblasts following glucocorticoid treatment. To identify regulatory sites potentially deregulated in glucocorticoid-resistant ALL cells, they focused on glucocorticoid-receptoroccupied regions located in the vicinity of genes differentially modulated by glucocorticoid treatment in glucocorticoid-sensitive ALL cells compared with glucocorticoid-resistant leukemia lymphoblasts. These analyses yielded 462 glucocorticoid-bound lymphoid-specific open regions associated with 389 genes,
Cancer Cell 34, December 10, 2018 ª 2018 Elsevier Inc. 869
Cancer Cell
Previews
Figure 1. Epigenetic Control of the BCL2L11 IGR Enhancer Controls Glucocorticoid-Induced BIM Upregulation and Programmed Cell Death
In non-lymphoid tissues, the BCL2L11 locus shows an inactive chromatin configuration at IGR which precludes glucocorticoid receptor binding and glucocorticoid-induced transcriptional activation, while lymphoid cells show accessible chromatin at this site. Glucocorticoid-sensitive ALL lymphoblasts show low levels of IGR methylation, that responds to glucocorticoid receptor binding with increased H3K27 acetylation, CTCF binding and looping to the BCL2L11 promoter to drive transcriptional activation and BIM upregulation with consequent activation of glucocorticoid-induced cell death. In contrast, glucocorticoid resistance is associated with increased enhancer methylation, decreased IGR accessibility, impaired glucocorticoid receptor binding, and failure to induce H3K27 acetylation, CTCF binding, and enhancer-promoter chromatin looping. By restoring a glucocorticoid-sensitive chromatin configuration at the BCL2L11 IGR enhancer, DNA demethylating agents can reverse glucocorticoid resistance. TSS, transcription start site.
of which 198 were upregulated and 191 were downregulated by glucocorticoid treatment only in glucocorticoid-sensitive cells. Epigenetic characterization of the chromatin landscape at these sites showed blunted changes in H3K27 acetylation in resistant cells. Moreover, DNA methylation and ATAC-seq profiling identified 42 glucocorticoid receptor interacting lymphoid-specific chromatin open regions harboring features of inactive chromatin—increased DNA methylation and reduced chromatin accessibility—in glucocorticoid-resistant leukemia cells. Extended ATAC-seq analysis in a broader panel of glucocorticoid sensitive and resistant ALL xenograft samples showed largely concordant results in support of a potential general role for impaired glucocorticoid-induced regulation of chromatin accessibility at these sites in glucocorticoid resistance. Notably, one of the glucocorticoid-bound lymphoid-specific open regions deregulated in resistant lymphoblasts corresponds to an intronic enhancer at the BCL2L11 locus. Functional characterization of this intronic glucocorticoid receptor-binding region (IGR) showed glucocorticoid-induced NR3C1 binding, increased chromatin accessibility and histone acetylation, as 870 Cancer Cell 34, December 10, 2018
well as glucocorticoid-induced transcriptional activation in reporter assays. Distal enhancers interact with and control the activity of proximal promoters via long-range chromatin loops in association with cohesin complexes and the CCCTC-binding factor CTCF. Consistently, analysis of CTCF occupancy showed increased binding by CTCF at the BCL2L11 IGR enhancer in sensitive cells treated with glucocorticoids, which correlated with the establishment of readily detectable promoter-enhancer interactions in chromosome conformation capture (3C) assays. Most notably, glucocorticoid-resistant lymphoblasts showed loss of CTCF binding in basal conditions and upon glucocorticoid treatment, which correlated with abrogation of glucocorticoid-induced BCL2L11 promoterenhancer interaction and transcriptional upregulation. A direct mechanistic role for the IGR enhancer is supported by loss of glucocorticoid-induced BCL2L11 transcriptional activation and cell death in glucocorticoid-sensitive cells after a focal deletion of this regulatory element. Chromatin accessibility is established by the activity of pioneering transcription factors, which can interact with nucleosomal DNA and mediate the recruitment of chro-
matin remodeling complexes to generate nucleosome-free regions accessible to transcription factor binding. Although the specific mechanisms responsible for lymphoid-restricted chromatin accessibility and activity of the BCL2L11 IGR remain to be fully elucidated, PU.1, a transcription factor described to have pioneering activity, interacts with this regulatory site in glucocorticoid-sensitive ALL cells and shows decreased binding in resistant lymphoblasts. In addition, DNA methylation at the IGR was increased in a broad panel of glucocorticoid-resistant leukemia xenografts supporting a role for DNA methylation in setting an inactive chromatin configuration. Consistent with this hypothesis, treatment of glucocorticoid-resistant ALL cells with 5-azacitidine, a DNA demethylating agent, reversed DNA methylation at this site, enhanced glucocorticoid-induced BCL2L11 upregulation, and enhanced glucocorticoid response in vitro. Concordantly, treatment with decitabine, a clinical DNA demethylating drug, showed increased therapeutic activity in combination with glucocorticoid treatment in vivo. Although much remains to be learned about epigenetic mechanisms in glucocorticoid resistance, this study underscores a
Cancer Cell
Previews potential role for local epigenetic-mediated silencing of the BCL2L11 IGR and potentially other glucocorticoid-controlled regulatory sites in glucocorticoid resistance. Importantly DNA methylation can alter CTCF binding, potentially linking increased focal methylation at the IGR with impaired enhancer-promoter looping. In addition, changes in chromatin accessibility could also be linked with DNA methylation, and the role of pioneering factors at this site remains to be fully explored. PU.1 binds to the IGR, yet PU.1 is prominently expressed in myeloid cells where the BCL2L11 IGR adopts a closed inactive chromatin configuration. Finally, it will be important to analyze the role of epigenetic heterogeneity and Darwinian selection of epi-alleles as drivers of glucocorticoid resistance in relapsed ALL (Ferrando and Lo´pez-Otı´n, 2017) and the potential role of this proposed mechanism in the response and resistance to glucocorticoid therapy in other lymphoid tumors.
REFERENCES Ferrando, A.A., and Lo´pez-Otı´n, C. (2017). Clonal evolution in leukemia. Nat. Med. 23, 1135–1145. Hunger, S.P., and Mullighan, C.G. (2015). Acute lymphoblastic leukemia in children. N. Engl. J. Med. 373, 1541–1552. Inaba, H., and Pui, C.H. (2010). Glucocorticoid use in acute lymphoblastic leukaemia. Lancet Oncol. 11, 1096–1106. Jing, D., Huang, Y., Liu, X., Sia, K.C.S., Zhang, J.C., Tai, X., Wang, M., Toscan, C.E., McCalmont, H., Evans, K., et al. (2018). Lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in acute lymphoblastic leukemia. Cancer Cell 34, this issue, 906–921. Mullighan, C.G., Zhang, J., Kasper, L.H., Lerach, S., Payne-Turner, D., Phillips, L.A., Heatley, S.L., Holmfeldt, L., Collins-Underwood, J.R., Ma, J., et al. (2011). CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature 471, 235–239. Oshima, K., Khiabanian, H., da Silva-Almeida, A.C., Tzoneva, G., Abate, F., Ambesi-Impiombato, A., Sanchez-Martin, M., Carpenter, Z., Penson, A., Perez-Garcia, A., et al. (2016). Mutational landscape, clonal evolution patterns, and role of
RAS mutations in relapsed acute lymphoblastic leukemia. Proc. Natl. Acad. Sci. USA 113, 11306–11311. Piovan, E., Yu, J., Tosello, V., Herranz, D., AmbesiImpiombato, A., Da Silva, A.C., Sanchez-Martin, M., Perez-Garcia, A., Rigo, I., Castillo, M., et al. (2013). Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia. Cancer Cell 24, 766–776. Real, P.J., Tosello, V., Palomero, T., Castillo, M., Hernando, E., de Stanchina, E., Sulis, M.L., Barnes, K., Sawai, C., Homminga, I., et al. (2009). Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat. Med. 15, 50–58. Wang, Z., Malone, M.H., He, H., McColl, K.S., and Distelhorst, C.W. (2003). Microarray analysis uncovers the induction of the proapoptotic BH3only protein Bim in multiple models of glucocorticoid-induced apoptosis. J. Biol. Chem. 278, 23861–23867. Wei, G., Twomey, D., Lamb, J., Schlis, K., Agarwal, J., Stam, R.W., Opferman, J.T., Sallan, S.E., den Boer, M.L., Pieters, R., et al. (2006). Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. Cancer Cell 10, 331–342.
From Basic Knowledge to Effective Therapies Daniel B. Lipka,1,2 Pavlo Lutsik,1 and Christoph Plass1,3,* 1Division
of Cancer Epigenomics, German Cancer Research Center, Heidelberg, Germany of Hematology and Oncology, Medical Center, Otto-von-Guericke-University, Magdeburg, Germany 3The German Cancer Research Consortium *Correspondence: [email protected] https://doi.org/10.1016/j.ccell.2018.11.013 2Department
In this issue of Cancer Cell, Ott et al. use integrative analysis of histone ChIP-seq and ATAC-seq to describe enhancer-based regulatory circuits in chronic lymphocytic leukemia. This work identified and validated transcription factor PAX5 as main driver of an oncogenic circuitry, which can be disrupted by BET bromodomain inhibition. Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia and is characterized by slowly proliferating B lymphocytes, which at the molecular level show defects in apoptosis. The clinical course of CLL is variable with indolent cases on one end and highly aggressive cases on the other end of the spectrum. Markers for aggressive forms of CLL include unmutated immunoglobulin heavy-chain variable region loci (IGHV) and aberrant expression of 70-kD zeta-associated protein
(ZAP-70), whereas indolent CLL cases show mutated IGHV and absence of ZAP-70 expression (Crespo et al., 2003). CLL is an excellent model system for basic and translational cancer research due to easy accessibility of malignant cells, the possibility to purify the malignant clones to highest purity, the availability of large cohorts of wellcharacterized biobanked samples from national and international clinical trials, and the availability of mouse models, recapitulating both indolent and aggres-
sive forms of the malignancy. Consequently, CLL has always been at the forefront of cancer research where the latest technologies have been applied in order to characterize the molecular defects underlying CLL pathogenesis. Very often, the information gained in such basic cancer research efforts has been translated into the clinic, either in form of novel diagnostic or prognostic models, or it has been used for the development of novel therapeutic approaches. This path is highlighted in
Cancer Cell 34, December 10, 2018 ª 2018 Elsevier Inc. 871