Gene expression profiles of B-lineage adult acute lymphocytic leukemia reveal genetic patterns that identify lineage derivation and distinct mechanisms of transformation

Sabina Chiaretti, Xiaochun Li, Robert Gentleman, Antonella Vitale, Kathy S. Wang, Franco Mandelli, Robin Foà, Jerome Ritz

Research output: Contribution to journalArticle

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Abstract

Purpose: To characterize gene expression signatures in acute lymphocytic leukemia (ALL) cells associated with known genotypic abnormalities in adult patients. Experimental Design: Gene expression profiles from 128 adult patients with newly diagnosed ALL were characterized using high-density oligonucleotide microarrays. All patients were enrolled in the Italian GIMEMA multicenter clinical trial 0496 and samples had >90% leukemic cells. Uniform phenotypic, cytogenetic, and molecular data were also available for all cases. Results: T-lineage ALL was characterized by a homogeneous gene expression pattern, whereas several subgroups of B-lineage ALL were evident. Within B-lineage ALL, distinct signatures were associated with ALL1/AF4 and E2A/PBX1 gene rearrangements. Expression profiles associated with ALL1/AF4 and E2A/PBX1 are similar in adults and children. BCR/ABL+ gene expression pattern was more heterogeneous and was most similar to ALL without known molecular rearrangements. We also identified a set of 83 genes that were highly expressed in leukemia blasts from patients without known molecular abnormalities who subsequently relapsed following therapy. Supervised analysis of kinase genes revealed a high-level FLT3 expression in a subset of cases without molecular rearrangements. Two other kinases (PRKCB1 and DDR1) were highly expressed in cases without molecular rearrangements, as well as in BCR/ABL-positive ALL. Conclusions: Genomic signatures are associated with phenotypically and molecularly well defined subgroups of adult ALL. Genomic profiling also identifies genes associated with poor outcome in cases without molecular aberrations and specific genes that may be new therapeutic targets in adult ALL.

Original languageEnglish (US)
Pages (from-to)7209-7219
Number of pages11
JournalClinical Cancer Research
Volume11
Issue number20
DOIs
StatePublished - Oct 15 2005
Externally publishedYes

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Transcriptome
Genes
Phosphotransferases
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Gene Expression
Gene Rearrangement
Oligonucleotide Array Sequence Analysis
Cytogenetics
Multicenter Studies
Leukemia
Research Design
Clinical Trials
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Gene expression profiles of B-lineage adult acute lymphocytic leukemia reveal genetic patterns that identify lineage derivation and distinct mechanisms of transformation. / Chiaretti, Sabina; Li, Xiaochun; Gentleman, Robert; Vitale, Antonella; Wang, Kathy S.; Mandelli, Franco; Foà, Robin; Ritz, Jerome.

In: Clinical Cancer Research, Vol. 11, No. 20, 15.10.2005, p. 7209-7219.

Research output: Contribution to journalArticle

Chiaretti, Sabina ; Li, Xiaochun ; Gentleman, Robert ; Vitale, Antonella ; Wang, Kathy S. ; Mandelli, Franco ; Foà, Robin ; Ritz, Jerome. / Gene expression profiles of B-lineage adult acute lymphocytic leukemia reveal genetic patterns that identify lineage derivation and distinct mechanisms of transformation. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 20. pp. 7209-7219.
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AU - Mandelli, Franco

AU - Foà, Robin

AU - Ritz, Jerome

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N2 - Purpose: To characterize gene expression signatures in acute lymphocytic leukemia (ALL) cells associated with known genotypic abnormalities in adult patients. Experimental Design: Gene expression profiles from 128 adult patients with newly diagnosed ALL were characterized using high-density oligonucleotide microarrays. All patients were enrolled in the Italian GIMEMA multicenter clinical trial 0496 and samples had >90% leukemic cells. Uniform phenotypic, cytogenetic, and molecular data were also available for all cases. Results: T-lineage ALL was characterized by a homogeneous gene expression pattern, whereas several subgroups of B-lineage ALL were evident. Within B-lineage ALL, distinct signatures were associated with ALL1/AF4 and E2A/PBX1 gene rearrangements. Expression profiles associated with ALL1/AF4 and E2A/PBX1 are similar in adults and children. BCR/ABL+ gene expression pattern was more heterogeneous and was most similar to ALL without known molecular rearrangements. We also identified a set of 83 genes that were highly expressed in leukemia blasts from patients without known molecular abnormalities who subsequently relapsed following therapy. Supervised analysis of kinase genes revealed a high-level FLT3 expression in a subset of cases without molecular rearrangements. Two other kinases (PRKCB1 and DDR1) were highly expressed in cases without molecular rearrangements, as well as in BCR/ABL-positive ALL. Conclusions: Genomic signatures are associated with phenotypically and molecularly well defined subgroups of adult ALL. Genomic profiling also identifies genes associated with poor outcome in cases without molecular aberrations and specific genes that may be new therapeutic targets in adult ALL.

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