Gene Expression Profiles of B-lineage Adult Acute Lymphocytic Leukemia Reveal Genetic Patterns that Identify Lineage Derivation and Distinct Mechanisms of Transformation

• Published in: Clinical cancer research Vol. 11; no. 20; pp. 7209 - 7219
• Main Authors: Chiaretti, Sabina, Li, Xiaochun, Gentleman, Robert, Vitale, Antonella, Wang, Kathy S., Mandelli, Franco, Foà, Robin, Ritz, Jerome
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.10.2005
• Subjects: acute lymphocytic leukemia; Adolescent; Adult; Biological and medical sciences; Burkitt Lymphoma - genetics; Burkitt Lymphoma - immunology; Burkitt Lymphoma - pathology; Cluster Analysis; Cytogenetic Analysis; Female; Flow Cytometry - methods; Gene expression profile; Gene Expression Profiling; Gene Expression Regulation, Leukemic - genetics; gene rearrangements; Hematologic and hematopoietic diseases; Humans; Immunophenotyping; Italy; Karyotyping; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Oligonucleotide Array Sequence Analysis - methods; Oncogene Proteins, Fusion - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - immunology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; tyrosine kinase genes; Italy; Human; Lymphoproliferative syndrome; Acute; Adult; Genetics; Malignant hemopathy; Identification; Acute lymphocytic leukemia; Mechanism of action; Gene expression profile
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-04-2165

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.