Developmental subtypes assessed by DNA methylation-iPLEX forecast the natural history of chronic lymphocytic leukemia

Brian Giacopelli, Qiuhong Zhao, Amy S. Ruppert, Akwasi Agyeman, Christoph Weigel, Yue Zhong Wu, Madelyn M. Gerber, Kari G. Rabe, Melissa C. Larson, Junyan Lu, James S. Blachly, Kerry A. Rogers, William G. Wierda, Jennifer R. Brown, Kanti R. Rai, Michael Keating, Laura Z. Rassenti, Thomas J. Kipps, Thorsten Zenz, Tait D. ShanafeltNeil E. Kay, Lynne V. Abruzzo, Kevin R. Coombes, Jennifer A. Woyach, John C. Byrd, Christopher C. Oakes

Research output: Contribution to journalArticle

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Abstract

Alterations in global DNA methylation patterns are a major hallmark of cancer and represent attractive biomarkers for personalized risk stratification. Chronic lymphocytic leukemia (CLL) risk stratification studies typically focus on time to first treatment (TTFT), time to progression (TTP) after treatment, and overall survival (OS). Whereas TTFT risk stratification remains similar over time, TTP and OS have changed dramatically with the introduction of targeted therapies, such as the Bruton tyrosine kinase inhibitor ibrutinib. We have shown that genome-wide DNA methylation patterns in CLL are strongly associated with phenotypic differentiation and patient outcomes. Here, we developed a novel assay, termed methylation-iPLEX (Me-iPLEX), for high-throughput quantification of targeted panels of single cytosine guanine dinucleotides from multiple independent loci. Me-iPLEX was used to classify CLL samples into 1 of 3 known epigenetic subtypes (epitypes). We examined the impact of epitype in 1286 CLL patients from 4 independent cohorts representing a comprehensive view of CLL disease course and therapies. We found that epitype significantly predicted TTFT and OS among newly diagnosed CLL patients. Additionally, epitype predicted TTP and OS with 2 common CLL therapies: chemoimmunotherapy and ibrutinib. Epitype retained significance after stratifying by biologically related biomarkers, immunoglobulin heavy chain mutational status, and ZAP70 expression, as well as other common prognostic markers. Furthermore, among several biological traits enriched between epitypes, we found highly biased immunogenetic features, including IGLV3-21 usage in the poorly characterized intermediate-programmed CLL epitype. In summary, Me-iPLEX is an elegant method to assess epigenetic signatures, including robust classification of CLL epitypes that independently stratify patient risk at diagnosis and time of treatment.

Original languageEnglish (US)
Pages (from-to)688-698
Number of pages11
JournalBlood
Volume134
Issue number8
DOIs
StatePublished - Aug 22 2019

Fingerprint

DNA Methylation
B-Cell Chronic Lymphocytic Leukemia
Methylation
Epigenomics
Biomarkers
Immunoglobulin Heavy Chains
Survival
Therapeutics
Assays
Genes
Throughput
Immunogenetics
Genome
PCI 32765

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Giacopelli, B., Zhao, Q., Ruppert, A. S., Agyeman, A., Weigel, C., Wu, Y. Z., ... Oakes, C. C. (2019). Developmental subtypes assessed by DNA methylation-iPLEX forecast the natural history of chronic lymphocytic leukemia. Blood, 134(8), 688-698. https://doi.org/10.1182/blood.2019000490

Developmental subtypes assessed by DNA methylation-iPLEX forecast the natural history of chronic lymphocytic leukemia. / Giacopelli, Brian; Zhao, Qiuhong; Ruppert, Amy S.; Agyeman, Akwasi; Weigel, Christoph; Wu, Yue Zhong; Gerber, Madelyn M.; Rabe, Kari G.; Larson, Melissa C.; Lu, Junyan; Blachly, James S.; Rogers, Kerry A.; Wierda, William G.; Brown, Jennifer R.; Rai, Kanti R.; Keating, Michael; Rassenti, Laura Z.; Kipps, Thomas J.; Zenz, Thorsten; Shanafelt, Tait D.; Kay, Neil E.; Abruzzo, Lynne V.; Coombes, Kevin R.; Woyach, Jennifer A.; Byrd, John C.; Oakes, Christopher C.

In: Blood, Vol. 134, No. 8, 22.08.2019, p. 688-698.

Research output: Contribution to journalArticle

Giacopelli, B, Zhao, Q, Ruppert, AS, Agyeman, A, Weigel, C, Wu, YZ, Gerber, MM, Rabe, KG, Larson, MC, Lu, J, Blachly, JS, Rogers, KA, Wierda, WG, Brown, JR, Rai, KR, Keating, M, Rassenti, LZ, Kipps, TJ, Zenz, T, Shanafelt, TD, Kay, NE, Abruzzo, LV, Coombes, KR, Woyach, JA, Byrd, JC & Oakes, CC 2019, 'Developmental subtypes assessed by DNA methylation-iPLEX forecast the natural history of chronic lymphocytic leukemia', Blood, vol. 134, no. 8, pp. 688-698. https://doi.org/10.1182/blood.2019000490
Giacopelli, Brian ; Zhao, Qiuhong ; Ruppert, Amy S. ; Agyeman, Akwasi ; Weigel, Christoph ; Wu, Yue Zhong ; Gerber, Madelyn M. ; Rabe, Kari G. ; Larson, Melissa C. ; Lu, Junyan ; Blachly, James S. ; Rogers, Kerry A. ; Wierda, William G. ; Brown, Jennifer R. ; Rai, Kanti R. ; Keating, Michael ; Rassenti, Laura Z. ; Kipps, Thomas J. ; Zenz, Thorsten ; Shanafelt, Tait D. ; Kay, Neil E. ; Abruzzo, Lynne V. ; Coombes, Kevin R. ; Woyach, Jennifer A. ; Byrd, John C. ; Oakes, Christopher C. / Developmental subtypes assessed by DNA methylation-iPLEX forecast the natural history of chronic lymphocytic leukemia. In: Blood. 2019 ; Vol. 134, No. 8. pp. 688-698.
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title = "Developmental subtypes assessed by DNA methylation-iPLEX forecast the natural history of chronic lymphocytic leukemia",
abstract = "Alterations in global DNA methylation patterns are a major hallmark of cancer and represent attractive biomarkers for personalized risk stratification. Chronic lymphocytic leukemia (CLL) risk stratification studies typically focus on time to first treatment (TTFT), time to progression (TTP) after treatment, and overall survival (OS). Whereas TTFT risk stratification remains similar over time, TTP and OS have changed dramatically with the introduction of targeted therapies, such as the Bruton tyrosine kinase inhibitor ibrutinib. We have shown that genome-wide DNA methylation patterns in CLL are strongly associated with phenotypic differentiation and patient outcomes. Here, we developed a novel assay, termed methylation-iPLEX (Me-iPLEX), for high-throughput quantification of targeted panels of single cytosine guanine dinucleotides from multiple independent loci. Me-iPLEX was used to classify CLL samples into 1 of 3 known epigenetic subtypes (epitypes). We examined the impact of epitype in 1286 CLL patients from 4 independent cohorts representing a comprehensive view of CLL disease course and therapies. We found that epitype significantly predicted TTFT and OS among newly diagnosed CLL patients. Additionally, epitype predicted TTP and OS with 2 common CLL therapies: chemoimmunotherapy and ibrutinib. Epitype retained significance after stratifying by biologically related biomarkers, immunoglobulin heavy chain mutational status, and ZAP70 expression, as well as other common prognostic markers. Furthermore, among several biological traits enriched between epitypes, we found highly biased immunogenetic features, including IGLV3-21 usage in the poorly characterized intermediate-programmed CLL epitype. In summary, Me-iPLEX is an elegant method to assess epigenetic signatures, including robust classification of CLL epitypes that independently stratify patient risk at diagnosis and time of treatment.",
author = "Brian Giacopelli and Qiuhong Zhao and Ruppert, {Amy S.} and Akwasi Agyeman and Christoph Weigel and Wu, {Yue Zhong} and Gerber, {Madelyn M.} and Rabe, {Kari G.} and Larson, {Melissa C.} and Junyan Lu and Blachly, {James S.} and Rogers, {Kerry A.} and Wierda, {William G.} and Brown, {Jennifer R.} and Rai, {Kanti R.} and Michael Keating and Rassenti, {Laura Z.} and Kipps, {Thomas J.} and Thorsten Zenz and Shanafelt, {Tait D.} and Kay, {Neil E.} and Abruzzo, {Lynne V.} and Coombes, {Kevin R.} and Woyach, {Jennifer A.} and Byrd, {John C.} and Oakes, {Christopher C.}",
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T1 - Developmental subtypes assessed by DNA methylation-iPLEX forecast the natural history of chronic lymphocytic leukemia

AU - Giacopelli, Brian

AU - Zhao, Qiuhong

AU - Ruppert, Amy S.

AU - Agyeman, Akwasi

AU - Weigel, Christoph

AU - Wu, Yue Zhong

AU - Gerber, Madelyn M.

AU - Rabe, Kari G.

AU - Larson, Melissa C.

AU - Lu, Junyan

AU - Blachly, James S.

AU - Rogers, Kerry A.

AU - Wierda, William G.

AU - Brown, Jennifer R.

AU - Rai, Kanti R.

AU - Keating, Michael

AU - Rassenti, Laura Z.

AU - Kipps, Thomas J.

AU - Zenz, Thorsten

AU - Shanafelt, Tait D.

AU - Kay, Neil E.

AU - Abruzzo, Lynne V.

AU - Coombes, Kevin R.

AU - Woyach, Jennifer A.

AU - Byrd, John C.

AU - Oakes, Christopher C.

PY - 2019/8/22

Y1 - 2019/8/22

N2 - Alterations in global DNA methylation patterns are a major hallmark of cancer and represent attractive biomarkers for personalized risk stratification. Chronic lymphocytic leukemia (CLL) risk stratification studies typically focus on time to first treatment (TTFT), time to progression (TTP) after treatment, and overall survival (OS). Whereas TTFT risk stratification remains similar over time, TTP and OS have changed dramatically with the introduction of targeted therapies, such as the Bruton tyrosine kinase inhibitor ibrutinib. We have shown that genome-wide DNA methylation patterns in CLL are strongly associated with phenotypic differentiation and patient outcomes. Here, we developed a novel assay, termed methylation-iPLEX (Me-iPLEX), for high-throughput quantification of targeted panels of single cytosine guanine dinucleotides from multiple independent loci. Me-iPLEX was used to classify CLL samples into 1 of 3 known epigenetic subtypes (epitypes). We examined the impact of epitype in 1286 CLL patients from 4 independent cohorts representing a comprehensive view of CLL disease course and therapies. We found that epitype significantly predicted TTFT and OS among newly diagnosed CLL patients. Additionally, epitype predicted TTP and OS with 2 common CLL therapies: chemoimmunotherapy and ibrutinib. Epitype retained significance after stratifying by biologically related biomarkers, immunoglobulin heavy chain mutational status, and ZAP70 expression, as well as other common prognostic markers. Furthermore, among several biological traits enriched between epitypes, we found highly biased immunogenetic features, including IGLV3-21 usage in the poorly characterized intermediate-programmed CLL epitype. In summary, Me-iPLEX is an elegant method to assess epigenetic signatures, including robust classification of CLL epitypes that independently stratify patient risk at diagnosis and time of treatment.

AB - Alterations in global DNA methylation patterns are a major hallmark of cancer and represent attractive biomarkers for personalized risk stratification. Chronic lymphocytic leukemia (CLL) risk stratification studies typically focus on time to first treatment (TTFT), time to progression (TTP) after treatment, and overall survival (OS). Whereas TTFT risk stratification remains similar over time, TTP and OS have changed dramatically with the introduction of targeted therapies, such as the Bruton tyrosine kinase inhibitor ibrutinib. We have shown that genome-wide DNA methylation patterns in CLL are strongly associated with phenotypic differentiation and patient outcomes. Here, we developed a novel assay, termed methylation-iPLEX (Me-iPLEX), for high-throughput quantification of targeted panels of single cytosine guanine dinucleotides from multiple independent loci. Me-iPLEX was used to classify CLL samples into 1 of 3 known epigenetic subtypes (epitypes). We examined the impact of epitype in 1286 CLL patients from 4 independent cohorts representing a comprehensive view of CLL disease course and therapies. We found that epitype significantly predicted TTFT and OS among newly diagnosed CLL patients. Additionally, epitype predicted TTP and OS with 2 common CLL therapies: chemoimmunotherapy and ibrutinib. Epitype retained significance after stratifying by biologically related biomarkers, immunoglobulin heavy chain mutational status, and ZAP70 expression, as well as other common prognostic markers. Furthermore, among several biological traits enriched between epitypes, we found highly biased immunogenetic features, including IGLV3-21 usage in the poorly characterized intermediate-programmed CLL epitype. In summary, Me-iPLEX is an elegant method to assess epigenetic signatures, including robust classification of CLL epitypes that independently stratify patient risk at diagnosis and time of treatment.

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