Lack of SSBP2, a Candidate Leukemia Suppressor, Promotes T Cell Lymphomagenesis in p53 Null Mice.

Our laboratory positionally cloned a candidate myeloid leukemia suppressor gene, sequence-specific single-stranded DNA binding protein 2 (SSBP2) from chromosome 5q13.3-5q14.1 interval. SSBP2 expression is lost in primary acute myelogenous leukemia (AML) and myelodysplasia (MDS) cells. AML cells induced to express SSBP2 show growth arrest and partial differentiation. SSBP2 directly binds the adaptor protein Ldb1 (LIM domain-binding protein1), which in turn binds LIM domain containing nuclear factors. Although LDB1, SSBP2 containing transcriptional complexes are ubiquitously expressed, they have been best characterized in erythroid differentiation. Stabilization of Ldb1 by its direct interaction with SSBP2 upregulated the transcriptional activity of the Ldb1-Lmo2-E2A/TAL1-containing complex on an erythroid specific gene promoter. Here, we report the generation and characterization of Ssbp2 null mice. Mice with homozygous disruption of Ssbp2 (Ssbp2^−/−) are viable and fertile, with no gross hematopoietic abnormalities observed up to six months of age. In order to examine if and how loss of SSBP2 promotes transformation, we crossed Ssbp2^−/− mice with p53^−/− null mice. Ssbp2^−/−, p53^−/− mice succumbed to thymic lymphomas with a median survival of 122 days compared to a median survival of 182 days for p53^−/− mice (P = 0.0002). Moreover, the spectrum of tumors observed in the Ssbp2^−/−, p53^−/− mice included 62.5% thymic lymphomas (20/32), whereas only 26.7% of the p53^−/− mice developed thymic lymphomas (8/30). In addition, Ldb1 protein levels but not transcript levels were decreased in the thymi of Ssbp2^−/−, and Ssbp2^−/−, p53^−/− mice. Thus, loss of Ssbp2 appears to abrogate Ldb1-Lmo2-mediated T cell differentiation by promoting Ldb1 degradation. Such a block in differentiation cooperates with the loss of cell cycle arrest and apoptosis due to loss of p53. Our findings demonstrate for the first time a functional cooperation between the candidate leukemia suppressor SSBP2 and tumor suppressor p53. Furthermore, these results suggest the Ldb1-Lmo2 complexes to be novel targets for therapeutic intervention in hematologic malignancies.