Engineered Bcor mutations lead to acute leukemia of progenitor B-1 lymphocyte origin in a sensitized background.

Approximately 10% of mice develop an aggressive acute lymphoblastic leukemia of B-1 lymphocyte progenitor origin (pro-B1 ALL), accompanied by somatic frameshift mutations of the BCL6 interacting corepressor () gene, most commonly within a 9-bp "hotspot" in exon 8. To determine whether experimentally engineered mutations would lead to pro-B1 ALL, we used clustered, regularly interspaced, short palindromic repeats-associated protein 9 to introduce a frameshift mutation into hematopoietic stem and progenitor cells through the use of small guide RNAs ( sgRNAs). Recipient mice transplanted with bone marrow or fetal liver cells that had been transduced with a sgRNA developed pro-B1 ALL, characterized by a B-1 progenitor immunophenotype, clonal Igh gene rearrangement, and indel mutation, whereas control recipients did not. Similar to a subset of human B-cell precursor ALL, the murine pro-B1 ALL had acquired somatic mutations in Jak kinase genes. JAK inhibitors (ruxolitinib and tofacitinib) inhibited the growth of pro-B1 ALL cell lines established from Bcor sgRNA/NP23 recipients at clinically achievable concentrations (100 nM). Our results demonstrate that mutations collaborate with to induce pro-B1 ALL, and that JAK inhibitors are potential therapies for pro-B1 ALL.