Progenitor B-1 B-cell acute lymphoblastic leukemia is associated with collaborative mutations in 3 critical pathways.

B-1 and B-2 lymphocytes are derived from distinct developmental pathways and represent layered arms of the innate and adaptive immune systems, respectively. In contrast to a majority of murine B-cell malignancies, which stain positive with the B220 antibody, we discovered a novel form of B-cell leukemia in - () transgenic mice. The immunophenotype (Lin B220 CD19 AA4.1) was identical to that of progenitor (pro) B-1 cells, and V gene usage was skewed toward 3' V regions, similar to murine fetal liver B cells. Moreover, the gene expression profile of these leukemias was most similar to that of fetal liver pro-B fraction BC, a known source of B-1 B cells, further supporting a pro-B-1 origin of these leukemias. The pro-B-1 acute lymphoblastic leukemias (ALLs) acquired spontaneous mutations in both and Janus kinase () pathway (// and ) genes, supporting a hypothesis that mutations in 3 critical pathways (stem-cell self-renewal, B-cell differentiation, and cytokine signaling) collaborate to induce B-cell precursor (BCP) ALL. Finally, the thymic stromal lymphopoietin (Tslp) cytokine is required for murine B-1 development, and chromosomal rearrangements resulting in overexpression of the TSLP receptor (CRLF2) are present in some patients with high-risk BCP-ALL (referred to as r ALL). Gene expression profiles of pro-B-1 ALL were more similar to that of r ALL than non-r ALL, and analysis of V gene usage from patients with ALL demonstrated preferential usage of V regions used by human B-1 B cells, leading to the suggestion that this subset of patients with BCP-ALL has a malignancy of B-1, rather than B-2, B-cell origin.