A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma

S Winandy, P Wu, K Georgopoulos - Cell, 1995 - cell.com
S Winandy, P Wu, K Georgopoulos
Cell, 1995cell.com
The lkaros gene is essential for lymphoid lineage specification. As previously reported, mice
homozygous for a mutation in the lkaros DNA-binding domain fail to generate mature
lymphocytes as well as their earliest described progenitors. In addition, our studies with mice
heterozygous for this mutation establish the lkaros gene as an essential regulator of T cell
proliferation. Thymocytes display augmented TCR-mediated proliferative responses, and
peripheral T cells are autoproliferative. A general lymphoproliferation precedes the T cell …
Summary
The lkaros gene is essential for lymphoid lineage specification. As previously reported, mice homozygous for a mutation in the lkaros DNA-binding domain fail to generate mature lymphocytes as well as their earliest described progenitors. In addition, our studies with mice heterozygous for this mutation establish the lkaros gene as an essential regulator of T cell proliferation. Thymocytes display augmented TCR-mediated proliferative responses, and peripheral T cells are autoproliferative. A general lymphoproliferation precedes the T cell leukemia and lymphoma that rapidly develop in all heterozygotes. The first step toward leukemic transformation occurs within the maturing thymocyte population and is demarcated by clonal expansions and loss of the single lkaros wild-type allele. From thesestudies, we proposethat within developing and mature T lymphocytes, distinct thresholds of lkaros activity are required to regulate proliferation. A decrease in lkaros activity below the first threshold causes the rapid accumulation of T lymphoblasts, whereas a further decrease leads to neoplastic transformation.
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