While PAX5 is an important tumor suppressor gene in B‐cell acute lymphoblastic leukemia (B‐ALL), it is also involved in oncogenic translocations coding for diverse 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 the PAX5‐JAK2 fusion protein in a mouse model expressing it from the endogenous Pax5 locus, resulting in inactivation of one of the two Pax5 alleles. Pax5Jak2/+ mice rapidly developed an aggressive B‐ALL in the absence of another cooperating exogenous gene mutation. The DNA‐binding function and kinase activity of Pax5‐Jak2 as well as IL‐7 signaling contributed to leukemia development. Interestingly, all Pax5Jak2/+ tumors lost the remaining 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, high levels of active phosphorylated STAT5 and increased expression of STAT5 target genes were seen in Pax5Jak2/+ B‐ALL tumors, implying that nuclear Pax5‐Jak2 phosphorylates STAT5. Together, these data reveal Pax5‐Jak2 as an important nuclear driver of leukemogenesis by maintaining phosphorylated STAT5 levels in the nucleus. Synopsis The oncogenic human PAX5‐JAK2 translocation encodes a protein consisting of the PAX5 DNA‐binding region fused to the constitutively active JAK2 kinase domain. A mouse model shows how this translocation promotes rapid development of aggressive B‐cell acute lymphoblastic leukemia (B‐ALL) in the absence of other exogenous mutations. Leukemogenesis in Pax5Jak2/+ mice depends on the DNA‐binding function and kinase activity of PAX5‐JAK2 and on IL‐7 signaling. Rapid tumorigenesis onset correlates with, and is accelerated by, loss of the wild‐type Pax5 allele. Loss of Pax5 facilitates DNA binding of PAX5‐JAK2. PAX5‐JAK2 does not act as a transcriptional or epigenetic regulator in the nucleus. PAX5‐JAK2 is a constitutively‐active nuclear kinase maintaining activation of the transcriptional leukemogenesis driver STAT5. A mouse model of the oncogenic PAX5‐JAK2 translocation reveals promotion of aggressive B‐ALL not via transcriptional or epigenetic alterations, but via increased phosphorylation and activation of the JAK2 target STAT5.