PXD006921

PXD006921 is an original dataset announced via ProteomeXchange.

Title	Splicing factor Ybx1 maintains persistent Jak2-mutated neoplasms via Mknk1-ERK-signaling
Description	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.
HostingRepository	PRIDE
AnnounceDate	2020-08-20
AnnouncementXML	Submission_2020-11-27_07:59:14.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mario Oroshi
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2017-07-10 23:35:35	ID requested
1	2020-08-20 00:28:24	announced
⏵ 2	2020-11-27 07:59:15	announced	2020-11-27: Updated publication reference for PubMed record(s): 33239784.

Jayavelu AK, Schn, ö, der TM, Perner F, Herzog C, Meiler A, Krishnamoorthy G, Huber N, Mohr J, Edelmann-Stephan B, Austin R, Brandt S, Palandri F, Schr, ö, der N, Isermann B, Edlich F, Sinha AU, Ungelenk M, H, ü, bner CA, Zeiser R, Rahmig S, Waskow C, Coldham I, Ernst T, Hochhaus A, Jilg S, Jost PJ, Mullally A, Bullinger L, Mertens PR, Lane SW, Mann M, Heidel FH, Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms. Nature, 588(7836):157-163(2020) [pubmed]

submitter keyword: Splicing factor,Hematological Malignancy, MPN, JAK2, YBX1, ERKsignaling,Phosphoproteome

Prof.Matthias Mann
contact affiliation	MaxPlanck Insitute of Biochemistry, Munich,Germany
contact email	mmann@biochem.mpg.de
lab head
Mario Oroshi
contact affiliation	Proteomics
contact email	oroshi@biochem.mpg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD006921
     1. Label: PRIDE project
     2. Name: Splicing factor Ybx1 maintains persistent Jak2-mutated neoplasms via Mknk1-ERK-signaling