Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: Correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome

Richard C. Harvey, Charles G. Mullighan, Xuefei Wang, Kevin K. Dobbin, George S. Davidson, Edward J. Bedrick, I. Ming Chen, Susan R. Atlas, Huining Kang, Kerem Ar, Carla S. Wilson, Walker Wharton, Maurice Murphy, Meenakshi Devidas, Andrew J. Carroll, Michael J Borowitz, W. Paul Bowman, James R. Downing, Mary Relling, Jun YangDeepa Bhojwani, William L. Carroll, Bruce Camitta, Gregory H. Reaman, Malcolm Smith, Stephen P. Hunger, Cheryl L. Willman

Research output: Contribution to journalArticle

Abstract

To resolve the genetic heterogeneity within pediatric high-risk B-precursor acute lymphoblastic leukemia (ALL), a clinically defined poor-risk group with few known recurring cytogenetic abnormalities, we performed gene expression profiling in a cohort of 207 uniformly treated children with high-risk ALL. Expression profiles were correlated with genome-wide DNA copy number abnormalities and clinical and outcome features. Unsupervised clustering of gene expression profiling data revealed 8 unique cluster groups within these highrisk ALL patients, 2 of which were associated with known chromosomal translocations (t(1;19)(TCF3-PBX1) or MLL), and 6 of which lacked any previously known cytogenetic lesion. One unique cluster was characterized by high expression of distinct outlier genes AGAP1, CCNJ, CHST2/7, CLEC12A/B, and PTPRM; ERG DNA deletions; and 4-year relapse-free survival of 94.7% ± 5.1%, compared with 63.5% ± 3.7% for the cohort (P = .01). A second cluster, characterized by high expression of BMPR1B, CRLF2, GPR110, and MUC4; frequent deletion of EBF1, IKZF1, RAG1-2, and IL3RA-CSF2RA; JAK mutations and CRLF2 rearrangements (P <.0001); and Hispanic ethnicity (P <.001) had a very poor 4-year relapse-free survival (21.0% ± 9.5%; P <.001). These studies reveal striking clinical and genetic heterogeneity in high-risk ALL and point to novel genes that may serve as new targets for diagnosis, risk classification, and therapy.

Original languageEnglish (US)
Pages (from-to)4874-4884
Number of pages11
JournalBlood
Volume116
Issue number23
DOIs
StatePublished - Dec 2 2010

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Pediatrics
Gene Expression Profiling
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Gene expression
Genes
Genome
DNA
Genetic Heterogeneity
Recurrence
Genetic Translocation
Survival
Hispanic Americans
Cytogenetics
Chromosome Aberrations
Cluster Analysis
Mutation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling : Correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome. / Harvey, Richard C.; Mullighan, Charles G.; Wang, Xuefei; Dobbin, Kevin K.; Davidson, George S.; Bedrick, Edward J.; Chen, I. Ming; Atlas, Susan R.; Kang, Huining; Ar, Kerem; Wilson, Carla S.; Wharton, Walker; Murphy, Maurice; Devidas, Meenakshi; Carroll, Andrew J.; Borowitz, Michael J; Bowman, W. Paul; Downing, James R.; Relling, Mary; Yang, Jun; Bhojwani, Deepa; Carroll, William L.; Camitta, Bruce; Reaman, Gregory H.; Smith, Malcolm; Hunger, Stephen P.; Willman, Cheryl L.

In: Blood, Vol. 116, No. 23, 02.12.2010, p. 4874-4884.

Research output: Contribution to journalArticle

Harvey, RC, Mullighan, CG, Wang, X, Dobbin, KK, Davidson, GS, Bedrick, EJ, Chen, IM, Atlas, SR, Kang, H, Ar, K, Wilson, CS, Wharton, W, Murphy, M, Devidas, M, Carroll, AJ, Borowitz, MJ, Bowman, WP, Downing, JR, Relling, M, Yang, J, Bhojwani, D, Carroll, WL, Camitta, B, Reaman, GH, Smith, M, Hunger, SP & Willman, CL 2010, 'Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: Correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome', Blood, vol. 116, no. 23, pp. 4874-4884. https://doi.org/10.1182/blood-2009-08-239681
Harvey, Richard C. ; Mullighan, Charles G. ; Wang, Xuefei ; Dobbin, Kevin K. ; Davidson, George S. ; Bedrick, Edward J. ; Chen, I. Ming ; Atlas, Susan R. ; Kang, Huining ; Ar, Kerem ; Wilson, Carla S. ; Wharton, Walker ; Murphy, Maurice ; Devidas, Meenakshi ; Carroll, Andrew J. ; Borowitz, Michael J ; Bowman, W. Paul ; Downing, James R. ; Relling, Mary ; Yang, Jun ; Bhojwani, Deepa ; Carroll, William L. ; Camitta, Bruce ; Reaman, Gregory H. ; Smith, Malcolm ; Hunger, Stephen P. ; Willman, Cheryl L. / Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling : Correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome. In: Blood. 2010 ; Vol. 116, No. 23. pp. 4874-4884.
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abstract = "To resolve the genetic heterogeneity within pediatric high-risk B-precursor acute lymphoblastic leukemia (ALL), a clinically defined poor-risk group with few known recurring cytogenetic abnormalities, we performed gene expression profiling in a cohort of 207 uniformly treated children with high-risk ALL. Expression profiles were correlated with genome-wide DNA copy number abnormalities and clinical and outcome features. Unsupervised clustering of gene expression profiling data revealed 8 unique cluster groups within these highrisk ALL patients, 2 of which were associated with known chromosomal translocations (t(1;19)(TCF3-PBX1) or MLL), and 6 of which lacked any previously known cytogenetic lesion. One unique cluster was characterized by high expression of distinct outlier genes AGAP1, CCNJ, CHST2/7, CLEC12A/B, and PTPRM; ERG DNA deletions; and 4-year relapse-free survival of 94.7{\%} ± 5.1{\%}, compared with 63.5{\%} ± 3.7{\%} for the cohort (P = .01). A second cluster, characterized by high expression of BMPR1B, CRLF2, GPR110, and MUC4; frequent deletion of EBF1, IKZF1, RAG1-2, and IL3RA-CSF2RA; JAK mutations and CRLF2 rearrangements (P <.0001); and Hispanic ethnicity (P <.001) had a very poor 4-year relapse-free survival (21.0{\%} ± 9.5{\%}; P <.001). These studies reveal striking clinical and genetic heterogeneity in high-risk ALL and point to novel genes that may serve as new targets for diagnosis, risk classification, and therapy.",
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T2 - Correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome

AU - Harvey, Richard C.

AU - Mullighan, Charles G.

AU - Wang, Xuefei

AU - Dobbin, Kevin K.

AU - Davidson, George S.

AU - Bedrick, Edward J.

AU - Chen, I. Ming

AU - Atlas, Susan R.

AU - Kang, Huining

AU - Ar, Kerem

AU - Wilson, Carla S.

AU - Wharton, Walker

AU - Murphy, Maurice

AU - Devidas, Meenakshi

AU - Carroll, Andrew J.

AU - Borowitz, Michael J

AU - Bowman, W. Paul

AU - Downing, James R.

AU - Relling, Mary

AU - Yang, Jun

AU - Bhojwani, Deepa

AU - Carroll, William L.

AU - Camitta, Bruce

AU - Reaman, Gregory H.

AU - Smith, Malcolm

AU - Hunger, Stephen P.

AU - Willman, Cheryl L.

PY - 2010/12/2

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N2 - To resolve the genetic heterogeneity within pediatric high-risk B-precursor acute lymphoblastic leukemia (ALL), a clinically defined poor-risk group with few known recurring cytogenetic abnormalities, we performed gene expression profiling in a cohort of 207 uniformly treated children with high-risk ALL. Expression profiles were correlated with genome-wide DNA copy number abnormalities and clinical and outcome features. Unsupervised clustering of gene expression profiling data revealed 8 unique cluster groups within these highrisk ALL patients, 2 of which were associated with known chromosomal translocations (t(1;19)(TCF3-PBX1) or MLL), and 6 of which lacked any previously known cytogenetic lesion. One unique cluster was characterized by high expression of distinct outlier genes AGAP1, CCNJ, CHST2/7, CLEC12A/B, and PTPRM; ERG DNA deletions; and 4-year relapse-free survival of 94.7% ± 5.1%, compared with 63.5% ± 3.7% for the cohort (P = .01). A second cluster, characterized by high expression of BMPR1B, CRLF2, GPR110, and MUC4; frequent deletion of EBF1, IKZF1, RAG1-2, and IL3RA-CSF2RA; JAK mutations and CRLF2 rearrangements (P <.0001); and Hispanic ethnicity (P <.001) had a very poor 4-year relapse-free survival (21.0% ± 9.5%; P <.001). These studies reveal striking clinical and genetic heterogeneity in high-risk ALL and point to novel genes that may serve as new targets for diagnosis, risk classification, and therapy.

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