title: Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia.
abstract: Human T cell leukemias can arise from oncogenes activated by specific chromosomal translocations involving the T cell receptor genes. Here we show that five different T cell oncogenes (HOX11, TAL1, LYL1, LMO1, and LMO2) are often aberrantly expressed in the absence of chromosomal abnormalities. Using oligonucleotide microarrays, we identified several gene expression signatures that were indicative of leukemic arrest at specific stages of normal thymocyte development: LYL1+ signature (pro-T), HOX11+ (early cortical thymocyte), and TAL1+ (late cortical thymocyte). Hierarchical clustering analysis of gene expression signatures grouped samples according to their shared oncogenic pathways and identified HOX11L2 activation as a novel event in T cell leukemogenesis. These findings have clinical importance, since HOX11 activation is significantly associated with a favorable prognosis, while expression of TAL1, LYL1, or, surprisingly, HOX11L2 confers a much worse response to treatment. Our results illustrate the power of gene expression profiles to elucidate transformation pathways relevant to human leukemia.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02142, USA.
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
authors.forename: Donna S
authors.initials: DS
authors.lastname: Neuberg
authors.forename: Jane
authors.initials: J
authors.lastname: Staunton
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.forename: Christine
authors.initials: C
authors.lastname: Huard
authors.forename: Susana C
authors.initials: SC
authors.lastname: Raimondi
authors.forename: Fred G
authors.initials: FG
authors.lastname: Behm
authors.forename: Ching Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000954:Antigens, Surface / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D060588:LIM Domain Proteins; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008667:Metalloproteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins; D015996:Survival Rate; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000954:Antigens, Surface; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; D008667:Metalloproteins; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C065072:LMO1 protein, human; C085117:LMO2 protein, human; C086541:LYL1 protein, human; C489494:TLX3 protein, human; C067143:TAL1 protein, human; C071250:TLX1 protein, human