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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 705-710
Altered lymphoid development in mice deficient for the mAF4
proto-oncogene
Patricia Isnard,
Nathalie Coré,
Philippe Naquet, and
Malek Djabali
From the Centre d'immunologie INSERM-CNRS de Marseille Luminy,
Marseille Cedex 9, France.
Some chromosomal translocations in acute leukemias involve the
fusion of the trithorax-related protein Mll (also called HRX, All1,
Htrx,) with a variety of heterologous proteins. In acute lymphoblastic
leukemia associated with the t(4;11)(q21;q23) translocation, the
4q21 gene that fuses with Mll is AF4. To gain insight
into the potential role of AF4 in leukemogenesis and
development, this gene was inactivated by homologous recombination in
mice. As expected from the tissue distribution of the AF4 transcript,
development of both B and T cells is affected in AF4 mutant mice. A
severe reduction of the thymic double positive CD4/CD8
(CD4+/CD8+) population was observed; in
addition most double- and single-positive cells expressed lower levels
of CD4 and CD8 coreceptors. Most importantly, the reconstitution of the
double-positive compartment by expansion of the double-negative cell
compartment was severely impaired in these mutant mice. In the bone
marrow pre-B and mature B-cell numbers are reduced. These results
demonstrate that the function of the mAF4 gene is critical for
normal lymphocyte development. This raises the possibility that
the disruption of the normal AF4 gene or its association
with Mll function by translocation may orient the oncogenic process
toward the lymphoid lineage. This represents the first functional
study using a knock-out strategy on one of the Mll partner genes
in translocation-associated leukemias.
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