GROWTH-STIMULATION OF PRIMARY B-CELL PRECURSORS BY THE ANTI-PHOSPHATASE SBF1

SET binding factor 1 (Sbf1) was originally discovered by virtue of its interaction with a highly conserved motif (the SET domain) of unknown function in the protoon-coprotein homolog of Drosophila trithorax, Hr x, Sbf1 shares extensive sequence similarity with myotubularin, a dual specificity phosphatase (dsPTPase) that is mutated in a subset of pat ients with inherited myopathies. Both Sbf1 and myotubularin interact w ith the SET domains of Hrx and other epigenetic regulatory proteins, b ut Sbf1 lacks phosphatase activity due to several evolutionarily conse rved amino acid changes in its structurally preserved catalytic pocket , Thus, Sbf1 has features of an anti-phosphatase that could competitiv ely antagonize dsPTPases; however the in vivo role for such factors re mains unknown, Given its ability to physically interact with Hrx, a de velopmental regulator subject to translocation-induced mutations in B cell precursor leukemias, the current studies were undertaken to asses s the effects of Sbf1 on lymphopoiesis, After infection with recombina nt Sbf1 retroviruses, bone marrow cells were plated under Whitlock-Wit te conditions for long-term culture of B lineage cells, Sbf1-expressin g cells rapidly dominated the cultures resulting in clonal outgrowths of B cell progenitors that retained a dependence on their primary bone marrow-derived stroma for continuous growth in vitro, Structure/funct ion analyses demonstrated that the SET interaction domain of Sbf1 was necessary and sufficient for growth alterations of B cell progenitors. These observations support a model in which Sbf1 functions as a SET d omain-dependent positive regulator of growth-inducing kinase signaling pathways that impinge on SET domain proteins. SET domain-dsPTPase int eractions appear to be critically important for regulating the growth properties of B cell progenitors.