Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia.
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.
Ferrando
Adolfo A
AA
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02142, USA.
Neuberg
Donna S
DS
Staunton
Jane
J
Loh
Mignon L
ML
Huard
Christine
C
Raimondi
Susana C
SC
Behm
Fred G
FG
Pui
Ching Hon
CH
Downing
James R
JR
Gilliland
D Gary
DG
Lander
Eric S
ES
Golub
Todd R
TR
Look
A Thomas
AT
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
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