Some chromosomal translocations in acute leukemias involve the fusion of th
e trithorax-related protein MII (also called HRX, All1, Htrx,) with a varie
ty of heterologous proteins. In acute lymphoblastic leukemia associated wit
h the t(4;11)(q21; q23) translocation, the 4q21 gene that fuses with MII 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, developmen
t 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 observ
ed; in addition most double- and single-positive cells expressed lower leve
ls of CD4 and CD8 coreceptors, Most importantly, the reconstitution of the
double-positive compartment by expansion of the double-negative cell compar
tment 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 f
unction of the mAF4 gene is critical for normal lymphocyte development. Thi
s raises the possibility that the disruption of the normal AF4 gene or its
association with MII function by translocation may orient the oncogenic pro
cess toward the lymphoid lineage. This represents the first functional stud
y using a knock-out strategy on one of the Mil partner genes in translocati
on-associated leukemias.