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

Abstract

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 <i>NUP98</i>-<i>PHF23</i> (<i>NP23</i>) transgenic mice. The immunophenotype (Lin^- B220^- CD19⁺ AA4.1⁺) was identical to that of progenitor (pro) B-1 cells, and V_H 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 <i>NP23</i> pro-B-1 acute lymphoblastic leukemias (ALLs) acquired spontaneous mutations in both <i>Bcor</i> and Janus kinase (<i>Jak</i>) pathway (<i>Jak1</i>/<i>2</i>/<i>3</i> and <i>Stat5a</i>) 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 <i>CRLF2</i>r ALL). Gene expression profiles of <i>NP23</i> pro-B-1 ALL were more similar to that of <i>CRLF2</i>r ALL than non-<i>CRLF2</i>r ALL, and analysis of V_H gene usage from patients with <i>CRLF2r</i> ALL demonstrated preferential usage of V_H 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.