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

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) δ-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 HOXU 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. The latter data, together with the clinical observations in t(10;14) T-ALL, suggest that T-cells expressing HOX11 are prone to undergo clonal expansions leading ultimately to lymphoid malignancy.

Key Words:

• HOX11
• Tlx-1
• leukemia
• homeobox genes
• T-ALL