4.8 Article

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

期刊

EMBO JOURNAL
卷 41, 期 7, 页码 -

出版社

WILEY
DOI: 10.15252/embj.2021108397

关键词

B-cell acute lymphoblastic leukemia; dual-hit mutation; mouse Pax5-Jak2 knock-in model; nuclear function of Pax5-Jak2; PAX5-JAK2 rearrangement

资金

  1. Boehringer Ingelheim
  2. Austrian Science Fund [P30814B28]
  3. Austrian Research Promotion Agency [FFG-878286]
  4. EMBO fellowship [ALTF 140-2013]

向作者/读者索取更多资源

PAX5 is an important tumor suppressor gene in B-cell acute lymphoblastic leukemia, but it is also involved in coding for various PAX5 fusion proteins. A study found that the PAX5-JAK2 fusion protein can promote leukemia development in a mouse model.
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. Pax5(Jak2/+) 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 Pax5(Jak2/+) 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 Pax5(Jak2/+) 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.

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