HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia (T-ALL).
Using a combination of molecular cytogenetic and large-scale expression analysis in human T-cell acute lymphoblastic leukemias (T-ALLs), we identified and characterized a new recurrent chromosomal translocation, targeting the major homeobox gene cluster HOXA and the TCRB locus. Real-time quantitative polymerase chain reaction (RQ-PCR) analysis showed that the expression of the whole HOXA gene cluster was dramatically dysregulated in the HOXA-rearranged cases, and also in MLL and CALM-AF10-related T-ALL cases, strongly suggesting that HOXA genes are oncogenic in these leukemias. Inclusion of HOXA-translocated cases in a general molecular portrait of 92 T-ALLs based on large-scale expression analysis shows that this rearrangement defines a new homogeneous subgroup, which shares common biologic networks with the TLX1- and TLX3-related cases. Because T-ALLs derive from T-cell progenitors, expression profiles of the distinct T-ALL subgroups were analyzed with respect to those of normal human thymic subpopulations. Inappropriate use or perturbation of specific molecular networks involved in thymic differentiation was detected. Moreover, we found a significant association between T-ALL oncogenic subgroups and ectopic expression of a limited set of genes, including several developmental genes, namely HOXA, TLX1, TLX3, NKX3-1, SIX6, and TFAP2C. These data strongly support the view that the abnormal expression of developmental genes, including the prototypical homeobox genes HOXA, is critical in T-ALL oncogenesis.
Soulier
Jean
J
Institut National de la Santé et de la Recherche Médicale Lymphocyte et Cancer, and Molecular Hematology Laboratory, Hôpital Saint Louis, Paris, France.
Clappier
Emmanuelle
E
Cayuela
Jean-Michel
JM
Regnault
Armelle
A
García-Peydró
Marina
M
Dombret
Hervé
H
Baruchel
André
A
Toribio
Maria-Luisa
ML
Sigaux
François
F
D000293:Adolescent; D000328:Adult; D000368:Aged; D002454:Cell Differentiation / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D005810:Multigene Family; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology; D014178:Translocation, Genetic
D018398:Homeodomain Proteins; C088144:HoxA protein