Integrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic strategies

Laura E. Hogan, Julia A. Meyer, Jun Yang, Jinhua Wang, Nicholas Wong, Wenjian Yang, Gregory Condos, Stephen P. Hunger, Elizabeth Raetz, Richard Saffery, Mary V. Relling, Deepa Bhojwani, Debra J. Morrison, William L. Carroll

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Despite an increase in survival for children with acute lymphoblastic leukemia (ALL), the outcome after relapse is poor. To understand the genetic events that contribute to relapse and chemoresistance and identify novel targets of therapy, 3 high-throughput assays were used to identify genetic and epigenetic changes at relapse. Using matched diagnosis/relapse bone marrow samples from children with relapsed B-precursor ALL, we evaluated gene expression, copy number abnormalities (CNAs), and DNA methylation. Gene expression analysis revealed a signature of differentially expressed genes from diagnosis to relapse that is different for early (< 36 months) and late (≥ 36 months) relapse. CNA analysis discovered CNAs that were shared at diagnosis and relapse and others that were new lesions acquired at relapse. DNA methylation analysis found increased promoter methylation at relapse. There were many genetic alterations that evolved from diagnosis to relapse, and in some cases these genes had previously been associated with chemoresistance. Integration of the results from all 3 platforms identified genes of potential interest, including CDKN2A, COL6A2, PTPRO, and CSMD1. Although our results indicate that a diversity of genetic changes are seen at relapse, integration of gene expression, CNA, and methylation data suggest a possible convergence on the WNT and mitogen-activated protein kinase pathways.

Original languageEnglish
Pages (from-to)5218-5226
Number of pages9
JournalBlood
Volume118
Issue number19
DOIs
Publication statusPublished - 10 Nov 2011
Externally publishedYes

Cite this

Hogan, Laura E. ; Meyer, Julia A. ; Yang, Jun ; Wang, Jinhua ; Wong, Nicholas ; Yang, Wenjian ; Condos, Gregory ; Hunger, Stephen P. ; Raetz, Elizabeth ; Saffery, Richard ; Relling, Mary V. ; Bhojwani, Deepa ; Morrison, Debra J. ; Carroll, William L. / Integrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic strategies. In: Blood. 2011 ; Vol. 118, No. 19. pp. 5218-5226.
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title = "Integrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic strategies",
abstract = "Despite an increase in survival for children with acute lymphoblastic leukemia (ALL), the outcome after relapse is poor. To understand the genetic events that contribute to relapse and chemoresistance and identify novel targets of therapy, 3 high-throughput assays were used to identify genetic and epigenetic changes at relapse. Using matched diagnosis/relapse bone marrow samples from children with relapsed B-precursor ALL, we evaluated gene expression, copy number abnormalities (CNAs), and DNA methylation. Gene expression analysis revealed a signature of differentially expressed genes from diagnosis to relapse that is different for early (< 36 months) and late (≥ 36 months) relapse. CNA analysis discovered CNAs that were shared at diagnosis and relapse and others that were new lesions acquired at relapse. DNA methylation analysis found increased promoter methylation at relapse. There were many genetic alterations that evolved from diagnosis to relapse, and in some cases these genes had previously been associated with chemoresistance. Integration of the results from all 3 platforms identified genes of potential interest, including CDKN2A, COL6A2, PTPRO, and CSMD1. Although our results indicate that a diversity of genetic changes are seen at relapse, integration of gene expression, CNA, and methylation data suggest a possible convergence on the WNT and mitogen-activated protein kinase pathways.",
author = "Hogan, {Laura E.} and Meyer, {Julia A.} and Jun Yang and Jinhua Wang and Nicholas Wong and Wenjian Yang and Gregory Condos and Hunger, {Stephen P.} and Elizabeth Raetz and Richard Saffery and Relling, {Mary V.} and Deepa Bhojwani and Morrison, {Debra J.} and Carroll, {William L.}",
year = "2011",
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doi = "10.1182/blood-2011-04-345595",
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Hogan, LE, Meyer, JA, Yang, J, Wang, J, Wong, N, Yang, W, Condos, G, Hunger, SP, Raetz, E, Saffery, R, Relling, MV, Bhojwani, D, Morrison, DJ & Carroll, WL 2011, 'Integrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic strategies' Blood, vol. 118, no. 19, pp. 5218-5226. https://doi.org/10.1182/blood-2011-04-345595

Integrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic strategies. / Hogan, Laura E.; Meyer, Julia A.; Yang, Jun; Wang, Jinhua; Wong, Nicholas; Yang, Wenjian; Condos, Gregory; Hunger, Stephen P.; Raetz, Elizabeth; Saffery, Richard; Relling, Mary V.; Bhojwani, Deepa; Morrison, Debra J.; Carroll, William L.

In: Blood, Vol. 118, No. 19, 10.11.2011, p. 5218-5226.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Meyer, Julia A.

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AU - Condos, Gregory

AU - Hunger, Stephen P.

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