Gprasp Family Members As Novel Regulators of B-Cell Development during Normal and Malignant Hematopoiesis

In our search for novel regulators of hematopoietic stem cell transplantation (HSCT), we recently reported Gprasp1 and Gprasp2 as negative regulators of HSCT. These genes encode proteins that are necessary for the stability, cellular trafficking and the proper degradation of CXCR4, a master regulator of hematopoiesis. Consequently, the absence of either Gprasp1 or Gprasp2 causes increased sensitivity to SDF-1 chemoattractant effect, enhancing HSCs repopulating activity after transplant. Strikingly, although Gprasp gene knockdown enhanced the repopulating activity of HSC at early time-points post-transplant, we observed that a significant number of mice transplanted with Gprasp-deficient hematopoietic progenitors developed an immature B-cell hematologic malignancy, typically at >20 weeks post-transplant. Since CXCR4 plays a crucial role in B-cell differentiation and, more specifically, in the movement of immature B-cells between the light and dark zones of the germinal center, we hypothesize that GPRASP family members are key regulators of CXCR4 during B-cell development during normal and malignant hematopoiesis. Thus, we followed mice transplanted with hematopoietic progenitors treated with control, Gprasp1 or Gprasp2-shRNAs for up to one year post-transplant. The onset of B-cell malignancy coincided with an accumulation of bone marrow common lymphoid progenitors, a complete disruption of the immunophenotype of B-cell progenitors and a loss of mature B-cells in the peripheral blood. Transformed cells invaded bone marrow, spleen, and lymph nodes in primary recipients. 100% of secondary recipients of leukemic cells developed a phenotypically identical malignancy <6 weeks post-transplant. As the dark zone of the geminal center is a region where somatic hypermutation is naturally exacerbated, we hypothesize that Gprasp-deficient B-cell progenitors are arrested in an immature state in the germinal center, increasing the likelihood of malignant transformation.