Dysregulation of HOX11 by chromosome translocations in T-cell acute lymphoblastic leukemia: a paradigm for homeobox gene involvement in human cancer.
The translocation t(10;14)(q24;q11) is observed in the course of routine cancer cytogenetic studies in 5-10% of patients with T-cell acute lymphoblastic leukemia (ALL). Recent molecular dissections of t(10;14) translocations support the hypothesis that these relatively gross chromosomal mutations represent key genetic steps in neoplastic transformation. The genes consistently involved are the T-cell receptor (TCR) delta-chain gene in 14q11 and a human homeobox-containing gene in 10q24, HOX11, initially identified through cloning of t(10;14) translocations. Like other homeoproteins, HOX11 binds DNA with sequence specificity and is likely to be a transcription factor, controlling the expression of developmentally important genes. The t(10;14) translocations arise as a result of aberrant physiological recombinational events that occur at early stages of T-cell development, probably during failed attempts at TCR gene rearrangement. The net result of the aberrant genetic recombinations is inappropriate expression of HOX11 in individual T-cells that acquire the mutation. Tlx-1, the murine homolog of HOX11, is expressed embryologically in the developing spleen and in structures derived from cranial neural crest cells and migratory paraxial mesoderm. Mice homozygously deleted for Tlx-1 are asplenic. Thus, HOX11 may be one of the first examples in mammals of a "master gene" acting as a regulatory switch controlling a downstream program of organ-specific cell growth and proliferation. Preliminary tumorigenicity assays suggest that HOX11 expression in hematopoietic cells most likely plays an immortalization role in neoplastic transformation.(ABSTRACT TRUNCATED AT 250 WORDS)
Lichty
B D
BD
Department of Cellular and Molecular Pathology, University of Toronto, Ontario, Canada.
Ackland-Snow
J
J
Noble
L
L
Kamel-Reid
S
S
Dubé
I D
ID
D005801:Genes, Homeobox; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics*; D014178:Translocation, Genetic