Splicing factor Ybx1 maintains persistent Jak2-mutated neoplasms via Mknk1-ERK-signaling

ABSTRACT: Janus kinases (Jak) mediate cytokine, hormone and growth factor responses in hematopoietic cells. Jak2 is one of the most frequently mutated genes in the aging hematopoietic system and in hematopoietic cancers. Mutations in Jak constitutively activate downstream signaling and are drivers of myeloproliferative neoplasms (MPN). In clinical use, Jak-inhibitors have incomplete effects on overall disease burden of Jak2 mutated clones, prompting us to investigate the mechanism underlying disease persistence. By in-depth phospho-proteome profiling we here identify proteins involved in mRNA processing as targets of mutant Jak2. Inactivation of the post-translationally modified Jak2-target Ybx1 sensitizes Jak-inhibitor persistent cells to apoptosis and results in RNA mis-splicing, retained intron enrichment and disruption of the transcriptional control of extracellular signal-regulated kinase (ERK) signaling. In combination with pharmacological Jak-inhibition it induces apoptosis in Jak2-dependent murine and primary human cells, leading to in vivo regression of the malignant clones and inducing remission. This identifies and validates a novel cell-intrinsic mechanism how differential protein phosphorylation results in splicing-dependent alterations of Jak2-ERK-signaling and the maintenance of Jak2V617F malignant clones. Therapeutic targeting of Ybx1 dependent ERK-signaling in combination with Jak2-inhibition may eradicate Jak2-mutated cells.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Multipotent Stem Cell, Primary Cell, Blood Cell, Monocyte, Leukocyte, Stem Cell, Cell Culture, Neutrophil, Bone Marrow, Blood

DISEASE(S): Myeloproliferative Neoplasm

SUBMITTER: Mario Oroshi  

LAB HEAD: Prof.Matthias Mann

PROVIDER: PXD006921 | Pride | 2020-08-20

REPOSITORIES: Pride