SSBP2, a candidate tumor suppressor gene, induces growth arrest and differentiation of myeloid leukemia cells

Abstract

Acute myelogenous leukemia (AML) is the most common leukemia in adults with clonal proliferation of myeloid stem cells. Two or more cooperating mechanisms, namely block in differentiation, enhanced proliferation and resistance to programmed cell death, underlie this neoplastic transformation. Nonrandom, complete and partial deletions of chromosome 5 are common anomalies in AML. Using positional cloning strategies, we characterized an evolutionarily conserved candidate myeloid leukemia suppressor gene encoding sequence-specific single-stranded DNA binding protein 2 (SSBP2) from chromosome 5q13.3, a locus that is frequently deleted in AML. Recent studies in Drosophila and Xenopus demonstrate a pivotal role for SSBPs in embryonic differentiation. In mammals, SSBP2 is one of three highly related and ubiquitously expressed genes. Here, we identify frequent loss of SSBP2 protein expression in human AML cell lines using highly specific antibodies. Furthermore, inducible expression of SSBP2 in the AML cell line U937 leads to loss of clonogenicity, G1 arrest and partial differentiation. Remarkably, inducible expression of SSBP2 is accompanied by downregulation of C-MYC expression. Our findings are consistent with human SSBP2 being a novel regulator of hematopoietic growth and differentiation, whose loss confers a block in differentiation advantage to myeloid leukemic cells.