Integrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic leukemia

Huimin Geng, Sarah Brennan, Thomas A. Milne, Wei Yi Chen, Yushan Li, Christian Hurtz, Soo Mi Kweon, Lynette Zickl, Seyedmehdi Shojaee, Donna Neuberg, Chuanxin Huang, Debabrata Biswas, Yuan Xin, Janis Racevskis, Rhett P. Ketterling, Selina M. Luger, Hillard Lazarus, Martin S. Tallman, Jacob M. Rowe, Mark R LitzowMonica L. Guzman, C. David Allis, Robert G. Roeder, Markus Müschen, Elisabeth Paietta, Olivier Elemento, Ari M. Melnick

Research output: Contribution to journalArticle

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Abstract

Genetic lesions such as BCR-ABL1, E2A-PBX1, and MLL rearrangements (MLLr) are associated with unfavorable outcomes in adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Leukemia oncoproteins may directly or indirectly disrupt cytosine methylation patterning to mediate the malignant phenotype. We postulated that DNA methylation signatures in these aggressive B-ALLs would point toward disease mechanisms and useful biomarkers and therapeutic targets. We therefore conducted DNA methylation and gene expression profiling on a cohort of 215 adult patients with B-ALL enrolled in a single phase III clinical trial (ECOG E2993) and normal control B cells. In BCR-ABL1 -positive B-ALLs, aberrant cytosine methylation patterning centered around a cytokine network defined by hypomethylation and overexpression of IL2RA (CD25). The E2993 trial clinical data showed that CD25 expression was strongly associated with a poor outcome in patients with ALL regardless of BCR-ABL1 status, suggesting CD25 as a novel prognostic biomarker for risk stratification in B-ALLs. In E2A-PBX1 -positive B-ALLs, aberrant DNA methylation patterning was strongly associated with direct fusion protein binding as shown by the E2A-PBX1 chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq), suggesting that E2A-PBX1 fusion protein directly remodels the epigenome to impose an aggressive B-ALL phenotype. MLL r B-ALL featured prominent cytosine hypomethylation, which was linked with MLL fusion protein binding, H3K79 dimethylation, and transcriptional upregulation, affecting a set of known and newly identified MLL fusion direct targets with oncogenic activity such as FLT3 and BCL6. Notably, BCL6 blockade or loss of function suppressed proliferation and survival of MLL r leukemia cells, suggesting BCL6-targeted therapy as a new therapeutic strategy for MLL r B-ALLs. SIGNIFICANCE: We conducted the first integrative epigenomic study in adult B-ALLs, as a correlative study to the ECOG E2993 phase III clinical trial. This study links for the first time the direct actions of oncogenic fusion proteins with disruption of epigenetic regulation mediated by cytosine methylation. We identify a novel clinically actionable biomarker in B-ALLs: IL2RA (CD25), which is linked with BCR- ABL1 and an inflammatory signaling network associated with chemotherapy resistance. We show that BCL6 is a novel MLL fusion protein target that is required to maintain the proliferation and survivalf primary human adult MLLr cells and provide the basis for a clinical trial with BCL6 inhibitors for patients with MLLr.

Original languageEnglish (US)
Pages (from-to)1006-1024
Number of pages19
JournalCancer Discovery
Volume2
Issue number11
DOIs
StatePublished - Nov 2012

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B-Lymphoid Precursor Cells
Cytosine
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Epigenomics
DNA Methylation
Biomarkers
Methylation
Phase III Clinical Trials
Protein Binding
Leukemia
Clinical Trials
Phenotype
Proteins
Chromatin Immunoprecipitation
Oncogene Proteins
Gene Expression Profiling
Therapeutics
B-Lymphocytes
Up-Regulation
Cytokines

ASJC Scopus subject areas

  • Oncology

Cite this

Geng, H., Brennan, S., Milne, T. A., Chen, W. Y., Li, Y., Hurtz, C., ... Melnick, A. M. (2012). Integrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic leukemia. Cancer Discovery, 2(11), 1006-1024. https://doi.org/10.1158/2159-8290.CD-12-0208

Integrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic leukemia. / Geng, Huimin; Brennan, Sarah; Milne, Thomas A.; Chen, Wei Yi; Li, Yushan; Hurtz, Christian; Kweon, Soo Mi; Zickl, Lynette; Shojaee, Seyedmehdi; Neuberg, Donna; Huang, Chuanxin; Biswas, Debabrata; Xin, Yuan; Racevskis, Janis; Ketterling, Rhett P.; Luger, Selina M.; Lazarus, Hillard; Tallman, Martin S.; Rowe, Jacob M.; Litzow, Mark R; Guzman, Monica L.; David Allis, C.; Roeder, Robert G.; Müschen, Markus; Paietta, Elisabeth; Elemento, Olivier; Melnick, Ari M.

In: Cancer Discovery, Vol. 2, No. 11, 11.2012, p. 1006-1024.

Research output: Contribution to journalArticle

Geng, H, Brennan, S, Milne, TA, Chen, WY, Li, Y, Hurtz, C, Kweon, SM, Zickl, L, Shojaee, S, Neuberg, D, Huang, C, Biswas, D, Xin, Y, Racevskis, J, Ketterling, RP, Luger, SM, Lazarus, H, Tallman, MS, Rowe, JM, Litzow, MR, Guzman, ML, David Allis, C, Roeder, RG, Müschen, M, Paietta, E, Elemento, O & Melnick, AM 2012, 'Integrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic leukemia', Cancer Discovery, vol. 2, no. 11, pp. 1006-1024. https://doi.org/10.1158/2159-8290.CD-12-0208
Geng, Huimin ; Brennan, Sarah ; Milne, Thomas A. ; Chen, Wei Yi ; Li, Yushan ; Hurtz, Christian ; Kweon, Soo Mi ; Zickl, Lynette ; Shojaee, Seyedmehdi ; Neuberg, Donna ; Huang, Chuanxin ; Biswas, Debabrata ; Xin, Yuan ; Racevskis, Janis ; Ketterling, Rhett P. ; Luger, Selina M. ; Lazarus, Hillard ; Tallman, Martin S. ; Rowe, Jacob M. ; Litzow, Mark R ; Guzman, Monica L. ; David Allis, C. ; Roeder, Robert G. ; Müschen, Markus ; Paietta, Elisabeth ; Elemento, Olivier ; Melnick, Ari M. / Integrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic leukemia. In: Cancer Discovery. 2012 ; Vol. 2, No. 11. pp. 1006-1024.
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abstract = "Genetic lesions such as BCR-ABL1, E2A-PBX1, and MLL rearrangements (MLLr) are associated with unfavorable outcomes in adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Leukemia oncoproteins may directly or indirectly disrupt cytosine methylation patterning to mediate the malignant phenotype. We postulated that DNA methylation signatures in these aggressive B-ALLs would point toward disease mechanisms and useful biomarkers and therapeutic targets. We therefore conducted DNA methylation and gene expression profiling on a cohort of 215 adult patients with B-ALL enrolled in a single phase III clinical trial (ECOG E2993) and normal control B cells. In BCR-ABL1 -positive B-ALLs, aberrant cytosine methylation patterning centered around a cytokine network defined by hypomethylation and overexpression of IL2RA (CD25). The E2993 trial clinical data showed that CD25 expression was strongly associated with a poor outcome in patients with ALL regardless of BCR-ABL1 status, suggesting CD25 as a novel prognostic biomarker for risk stratification in B-ALLs. In E2A-PBX1 -positive B-ALLs, aberrant DNA methylation patterning was strongly associated with direct fusion protein binding as shown by the E2A-PBX1 chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq), suggesting that E2A-PBX1 fusion protein directly remodels the epigenome to impose an aggressive B-ALL phenotype. MLL r B-ALL featured prominent cytosine hypomethylation, which was linked with MLL fusion protein binding, H3K79 dimethylation, and transcriptional upregulation, affecting a set of known and newly identified MLL fusion direct targets with oncogenic activity such as FLT3 and BCL6. Notably, BCL6 blockade or loss of function suppressed proliferation and survival of MLL r leukemia cells, suggesting BCL6-targeted therapy as a new therapeutic strategy for MLL r B-ALLs. SIGNIFICANCE: We conducted the first integrative epigenomic study in adult B-ALLs, as a correlative study to the ECOG E2993 phase III clinical trial. This study links for the first time the direct actions of oncogenic fusion proteins with disruption of epigenetic regulation mediated by cytosine methylation. We identify a novel clinically actionable biomarker in B-ALLs: IL2RA (CD25), which is linked with BCR- ABL1 and an inflammatory signaling network associated with chemotherapy resistance. We show that BCL6 is a novel MLL fusion protein target that is required to maintain the proliferation and survivalf primary human adult MLLr cells and provide the basis for a clinical trial with BCL6 inhibitors for patients with MLLr.",
author = "Huimin Geng and Sarah Brennan and Milne, {Thomas A.} and Chen, {Wei Yi} and Yushan Li and Christian Hurtz and Kweon, {Soo Mi} and Lynette Zickl and Seyedmehdi Shojaee and Donna Neuberg and Chuanxin Huang and Debabrata Biswas and Yuan Xin and Janis Racevskis and Ketterling, {Rhett P.} and Luger, {Selina M.} and Hillard Lazarus and Tallman, {Martin S.} and Rowe, {Jacob M.} and Litzow, {Mark R} and Guzman, {Monica L.} and {David Allis}, C. and Roeder, {Robert G.} and Markus M{\"u}schen and Elisabeth Paietta and Olivier Elemento and Melnick, {Ari M.}",
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T1 - Integrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic leukemia

AU - Geng, Huimin

AU - Brennan, Sarah

AU - Milne, Thomas A.

AU - Chen, Wei Yi

AU - Li, Yushan

AU - Hurtz, Christian

AU - Kweon, Soo Mi

AU - Zickl, Lynette

AU - Shojaee, Seyedmehdi

AU - Neuberg, Donna

AU - Huang, Chuanxin

AU - Biswas, Debabrata

AU - Xin, Yuan

AU - Racevskis, Janis

AU - Ketterling, Rhett P.

AU - Luger, Selina M.

AU - Lazarus, Hillard

AU - Tallman, Martin S.

AU - Rowe, Jacob M.

AU - Litzow, Mark R

AU - Guzman, Monica L.

AU - David Allis, C.

AU - Roeder, Robert G.

AU - Müschen, Markus

AU - Paietta, Elisabeth

AU - Elemento, Olivier

AU - Melnick, Ari M.

PY - 2012/11

Y1 - 2012/11

N2 - Genetic lesions such as BCR-ABL1, E2A-PBX1, and MLL rearrangements (MLLr) are associated with unfavorable outcomes in adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Leukemia oncoproteins may directly or indirectly disrupt cytosine methylation patterning to mediate the malignant phenotype. We postulated that DNA methylation signatures in these aggressive B-ALLs would point toward disease mechanisms and useful biomarkers and therapeutic targets. We therefore conducted DNA methylation and gene expression profiling on a cohort of 215 adult patients with B-ALL enrolled in a single phase III clinical trial (ECOG E2993) and normal control B cells. In BCR-ABL1 -positive B-ALLs, aberrant cytosine methylation patterning centered around a cytokine network defined by hypomethylation and overexpression of IL2RA (CD25). The E2993 trial clinical data showed that CD25 expression was strongly associated with a poor outcome in patients with ALL regardless of BCR-ABL1 status, suggesting CD25 as a novel prognostic biomarker for risk stratification in B-ALLs. In E2A-PBX1 -positive B-ALLs, aberrant DNA methylation patterning was strongly associated with direct fusion protein binding as shown by the E2A-PBX1 chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq), suggesting that E2A-PBX1 fusion protein directly remodels the epigenome to impose an aggressive B-ALL phenotype. MLL r B-ALL featured prominent cytosine hypomethylation, which was linked with MLL fusion protein binding, H3K79 dimethylation, and transcriptional upregulation, affecting a set of known and newly identified MLL fusion direct targets with oncogenic activity such as FLT3 and BCL6. Notably, BCL6 blockade or loss of function suppressed proliferation and survival of MLL r leukemia cells, suggesting BCL6-targeted therapy as a new therapeutic strategy for MLL r B-ALLs. SIGNIFICANCE: We conducted the first integrative epigenomic study in adult B-ALLs, as a correlative study to the ECOG E2993 phase III clinical trial. This study links for the first time the direct actions of oncogenic fusion proteins with disruption of epigenetic regulation mediated by cytosine methylation. We identify a novel clinically actionable biomarker in B-ALLs: IL2RA (CD25), which is linked with BCR- ABL1 and an inflammatory signaling network associated with chemotherapy resistance. We show that BCL6 is a novel MLL fusion protein target that is required to maintain the proliferation and survivalf primary human adult MLLr cells and provide the basis for a clinical trial with BCL6 inhibitors for patients with MLLr.

AB - Genetic lesions such as BCR-ABL1, E2A-PBX1, and MLL rearrangements (MLLr) are associated with unfavorable outcomes in adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Leukemia oncoproteins may directly or indirectly disrupt cytosine methylation patterning to mediate the malignant phenotype. We postulated that DNA methylation signatures in these aggressive B-ALLs would point toward disease mechanisms and useful biomarkers and therapeutic targets. We therefore conducted DNA methylation and gene expression profiling on a cohort of 215 adult patients with B-ALL enrolled in a single phase III clinical trial (ECOG E2993) and normal control B cells. In BCR-ABL1 -positive B-ALLs, aberrant cytosine methylation patterning centered around a cytokine network defined by hypomethylation and overexpression of IL2RA (CD25). The E2993 trial clinical data showed that CD25 expression was strongly associated with a poor outcome in patients with ALL regardless of BCR-ABL1 status, suggesting CD25 as a novel prognostic biomarker for risk stratification in B-ALLs. In E2A-PBX1 -positive B-ALLs, aberrant DNA methylation patterning was strongly associated with direct fusion protein binding as shown by the E2A-PBX1 chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq), suggesting that E2A-PBX1 fusion protein directly remodels the epigenome to impose an aggressive B-ALL phenotype. MLL r B-ALL featured prominent cytosine hypomethylation, which was linked with MLL fusion protein binding, H3K79 dimethylation, and transcriptional upregulation, affecting a set of known and newly identified MLL fusion direct targets with oncogenic activity such as FLT3 and BCL6. Notably, BCL6 blockade or loss of function suppressed proliferation and survival of MLL r leukemia cells, suggesting BCL6-targeted therapy as a new therapeutic strategy for MLL r B-ALLs. SIGNIFICANCE: We conducted the first integrative epigenomic study in adult B-ALLs, as a correlative study to the ECOG E2993 phase III clinical trial. This study links for the first time the direct actions of oncogenic fusion proteins with disruption of epigenetic regulation mediated by cytosine methylation. We identify a novel clinically actionable biomarker in B-ALLs: IL2RA (CD25), which is linked with BCR- ABL1 and an inflammatory signaling network associated with chemotherapy resistance. We show that BCL6 is a novel MLL fusion protein target that is required to maintain the proliferation and survivalf primary human adult MLLr cells and provide the basis for a clinical trial with BCL6 inhibitors for patients with MLLr.

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