The PAX5-JAK2 translocation acts as a dual-hit mutation that promotes aggressive B-cell leukemia via nuclear STAT5 activation

While PAX5 is an important tumor suppressor in B-ALL, it is also involved in oncogenic translocations coding for PAX5 fusion proteins. PAX5-JAK2 encodes a protein consisting of the PAX5 DNA-binding region fused to the constitutively active JAK2 kinase domain. Here, we studied the oncogenic function of PAX5-JAK2 in a mouse model expressing it from the endogenous Pax5 locus. The Pax5Jak2/+ mice rapidly developed an aggressive B-ALL in the absence of another cooperating mutation. The DNA-binding function and kinase activity of Pax5-Jak2, as well as IL-7 signaling, all contributed to leukemia development. Interestingly, all Pax5Jak2/+ tumors lost the wild-type Pax5 allele, allowing efficient DNA binding of Pax5-Jak2. While we could not find evidence for a nuclear role of Pax5-Jak2 as an epigenetic regulator, active phosphorylated Stat5 was present at a high level in Pax5Jak2/+ B-ALL tumors, consistent with increased expression of Stat5 target genes. Together, these data identified Pax5-Jak2 as an important nuclear driver of leukemia formation by maintaining phosphorylated Stat5 levels in the nucleus. Overall design: 6 Bio-ChIP-Seq samples, 2 experiments, 2 replicates per condition: experiment 1: 29936 + 29938 (wild type) experiment 2: 38870 + 40031 (experimental), 40030 + 40031 (control) 19 ChIP-Seq samples, 5 experiments: experiment 1: 100885-100883, 12 samples experiment 2: 138001 (input), 138002 (experimental), 138003 (control) experiment 3: 35059 + 35061 (wild type) experiment 4: 35327 (input) experiment 5: 8265 (wild type) 21 RNA-Seq samples, 4 experiments, 2-4 replicates each; experiment 1: 36328/36329, 36346-36348 (6 samples); experiment 2: 24394-24397 (4 samples); experiment 3: 38492-38497 (5 samples); experiment 4: 99560-99565 (6 samples)