PXD039419-1

PXD039419 is an original dataset announced via ProteomeXchange.

Title	Development of resistance to type II JAK2 inhibition in MPN depends on AXL kinase and is targetable
Description	Purpose: Myeloproliferative neoplasms (MPN) dysregulate JAK2 signaling. Since clinical JAK2 inhibitors have limited disease-modifying effects, type II JAK2 inhibitors such as CHZ868 stabilizing inactive JAK2 and reducing MPN clones, gain interest. We studied whether MPN cells escape from type ll inhibition. Methods: MPN cells were continuously exposed to CHZ868. We used phosphoproteomic analyses and ATAC-/RNA-sequencing to characterize acquired resistance to type II JAK2 inhibition, and targeted candidate mediators in MPN cells and mice. Results: MPN cells showed increased IC50 and reduced apoptosis upon CHZ868 reflecting acquired resistance to JAK2 inhibition. Among >2500 differential phospho-sites, MAPK pathway activation was most prominent, while JAK2-STAT3/5 remained suppressed. Altered histone occupancy promoting AP-1/GATA binding motif exposure associated with upregulated AXL kinase and enriched RAS target gene profiles. AXL knockdown resensitized MPN cells and combined JAK2/AXL inhibition using bemcentinib or gilteritinib reduced IC50 to levels of sensitive cells. While resistant cells induced tumor growth in NSG mice despite JAK2 inhibition, JAK2/AXL inhibition largely prevented tumor progression. Since inhibitors of MAPK pathway kinases such as MEK are clinically used in other malignancies, we evaluated JAK2/MAPK inhibition with trametinib to interfere with AXL-MAPK-induced resistance. Tumor growth was halted similarly to JAK2/AXL inhibition and in a systemic cell line-derived mouse model, marrow infiltration was decreased supporting dependency on AXL-MAPK. Conclusions: We report on a novel mechanism of AXL-MAPK-driven escape from type II JAK2 inhibition, which is targetable at different nodes. This highlights AXL as mediator of acquired resistance warranting inhibition to enhance sustainability of JAK2 inhibition in MPN
HostingRepository	PRIDE
AnnounceDate	2023-11-07
AnnouncementXML	Submission_2023-11-07_05:51:02.281.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	KatarzynaBuczak
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-01-13 07:21:31	ID requested
⏵ 1	2023-11-07 05:51:02	announced

Dataset with its publication pending

submitter keyword: : LFQ, resistance, myeloproliferative neoplasms, MAPK, CHZ868, AXL, phosphoproteomics, DDA, JAK2 inhibition

AlexanderSchmidt
contact affiliation	Proteomics Core Facility, Biozentrum, University of Basel
contact email	alex.schmidt@unibas.ch
lab head
KatarzynaBuczak
contact affiliation	Biozentrum, University of Basel
contact email	katarzyna.buczak@unibas.ch
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD039419
     1. Label: PRIDE project
     2. Name: Development of resistance to type II JAK2 inhibition in MPN depends on AXL kinase and is targetable