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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE174775 | GEO | 2022/02/04

REPOSITORIES: GEO

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

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

| PRJNA731504 | ENA

Ebf1 or Pax5 Haploinsufficiency Synergizes with STAT5 Activation to Initiate Acute Lymphoblastic Leukemia

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