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Loss of Function of the Homeobox Gene Hoxa-9 Perturbs Early
T-Cell Development and Induces Apoptosis in Primitive Thymocytes
David J. Izon,
Sofia Rozenfeld,
Stephen T. Fong,
László Kömüves,
Corey Largman, and
H. Jeffrey Lawrence
From the Division of Hematology/Medical Oncology, Department of
Medicine, and the Department of Dermatology, Veterans Affairs Medical
Center, University of California, San Francisco, CA.
Hox homeobox genes play a crucial role in specifying the
embryonic body 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 the Hoxa-9 gene are one eighth normal
size and have a 25-fold decrease in the number of primitive thymocytes expressing the interleukin-2 receptor (IL-2R, CD25). Progression to the
double positive (CD4+CD8+) stage is
dramatically retarded in fetal thymic organ cultures. This aberrant
development is associated with decreased amounts of intracellular CD3
and T-cell receptor  (TCR) and reduced surface
expression of IL-7R and E-cadherin. Mutant thymocytes show a
significant increase in apoptotic cell death and premature downregulation of bcl-2 expression. A similar phenotype is seen in
primitive thymocytes from adult Hoxa-9 / mice
and from mice transplanted with Hoxa-9/
marrow. Hoxa-9 appears to play a previously unsuspected role in
T-cell ontogeny by modulating cell survival of early thymocytes and by
regulating their subsequent differentiation.
Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 383-393
© 1998 by the American Society of Hematology.
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