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Blood, 1 July 2005, Vol. 106, No. 1, pp. 274-286.
Prepublished online as a Blood First Edition Paper on March 17, 2005; DOI 10.1182/blood-2004-10-3900.
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NEOPLASIA
HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia (T-ALL)
Jean Soulier,
Emmanuelle Clappier,
Jean-Michel Cayuela,
Armelle Regnault,
Marina García-Peydró,
Hervé Dombret,
André Baruchel,
Maria-Luisa Toribio, and
François Sigaux
From Institut National de la Santé et de la Recherche Médicale (INSERM) U462 `Lymphocyte et Cancer,' and Molecular Hematology Laboratory, Institut Universitaire d'Hématologie, Hôpital Saint Louis, Paris, France; Centro de Biología Molecular Severo Ochoa, CSIC, Universidad Autónoma de Madrid, Madrid, Spain; and Adult Hematology Department and Pediatric Hematology Department, Hôpital Saint Louis, Paris, France.
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.
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