LOSS OF FUNCTION OF THE HOMEOBOX GENE HOXA-9 PERTURBS EARLY T-CELL DEVELOPMENT AND INDUCES APOPTOSIS IN PRIMITIVE THYMOCYTES

Hox homeobox genes play a crucial role in specifying the embryonic bod y pattern. However, a role for Hox genes in T-cell development has not been explored. The Hoxa-9 gene is expressed in normal adult and fetal thymuses, Fetal thymuses of mice homozygous for an interruption of th e Hoxa-9 gene are one eighth normal size and have a 25-fold decrease i n the number of primitive thymocytes expressing the interleukin-2 rece ptor (IL-2R, CD25), Progression to the double positive (CD4(+)CD8(+)) stage is dramatically retarded in fetal thymic organ cultures. This ab errant development is associated with decreased amounts of intracellul ar CD3 and T-cell receptor beta (TCR beta) and reduced surface express ion of IL-7R and E-cadherin, Mutant thymocytes show a significant incr ease in apoptotic cell death and premature downregulation of bcl-2 exp ression. A similar phenotype is seen in primitive thymocytes from adul t Hoxa-9(-l-) mice and from mice transplanted with Hoxa-9(-l-) marrow. Hoxa-9 appears to play a previously unsuspected role in T-cell ontoge ny by modulating cell survival of early thymocytes and by regulating t heir subsequent differentiation. (C) 1998 by The American Society of H ematology.