Mice deficient for the Slp65 signaling protein: A model for Pre-B cell acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL) is characterized by oncogenic transformation of progenitors of the B-cell lineage in the bone marrow. Extensive molecular characterization of genetic abnormalities, in particular chromosomal translocations, have allowed the development of sensitive assays for the identification of underlying molecular defects that are applicable to ALL diagnosis and to monitor response to treatment. The need for further improvement of therapy requires in-depth understanding of the fundamental nature of the disease process and of mechanisms by which lymphoid cells undergo malignant transformation and progression. Research in this area is strongly facilitated by the availability of animal models. Mice deficient for the signaling molecule Slp65 spontaneously develop pre-B cell leukemia. Importantly, deficiency of SLP65 has been reported in a fraction of childhood precursor-B cell ALL cases. Moreover, in precursor-B ALL positive for the BCR-ABL translocation the activity of the BCR-ABL1 kinase fusion protein was linked to expression of the same aberrant SLP65 transcripts. In the B-cell lineage, diversity of the antibody repertoire is generated by recombination of various gene segments at the immunoglobulin (Ig) heavy (H) and light (L) chain loci, which occurs in an ordered manner. Signaling by membrane Ig governs a number of distinct checkpoints in B cell differentiation that shape the antibody repertoire. A central checkpoint is the pre-B cell receptor (pre-BCR), which monitors successful expression of the Ig H chain and signals for proliferation, differentiation and Ig L chain recombination. In pre-B cells cooperative signals initiated from the pre-BCR and the interleukin-7 receptor (IL-7R) govern pre-B cell proliferation. The adapter protein Slp65 and the cytoplasmic tyrosine kinase Btk are key components of signaling pathways downstream of the pre-BCR and cooperate as tumor suppressors. Slp65 is essential for cell cycle exit and developmental progression of large, cycling into small, resting pre-B cells in which Ig L chain recombination is initiated. At this transition, IL-7 responsiveness and expression of the c-myc oncogene is downregulated and the Bcl6 transcriptional repressor is activated, thereby protecting pre-B cells from DNA damage-induced apoptosis during Ig L chain gene recombination. In this review, we discuss recent findings that define the role of Slp65 in pre-B cell differentiation and give insight into molecular mechanisms by which Slp65-deficient pre-B cells undergo oncogenic transformation in the mouse.