Dysregulation of HOX11 by Chromosome Translocations in T-cell Acute Lymphoblastic Leukemia: A Paradigm for Homeobox Gene Involvement in Human Cancer Academic Article uri icon

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abstract

  • 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)

authors

  • Lichty, Brian
  • Ackland-Snow, Julia
  • Noble, Liliana
  • Kamel-Reid, Suzanne
  • Dube, Ian D

publication date

  • January 1995