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Metabolic Alterations in JAK2 Mutant Hematopoietic Cells Represent Therapeutic Vulnerabilities for Myeloproliferative Neoplasms

ABSTRACT: Metabolic Alterations in JAK2 Mutant Hematopoietic Cells Represent Therapeutic Vulnerabilities for Myeloproliferative Neoplasms

PROVIDER: PRJNA479424 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7467120.fastq.gz	Fastqsanger.gz
	SRR7467130.fastq.gz	Fastqsanger.gz
	SRR7467140.fastq.gz	Fastqsanger.gz
	SRR7467121.fastq.gz	Fastqsanger.gz
	SRR7467131.fastq.gz	Fastqsanger.gz

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Metabolic Alterations in JAK2 Mutant Hematopoietic Cells Represent Therapeutic Vulnerabilities for Myeloproliferative Neoplasms

Project description:Increased energy requirement and metabolic reprograming is a hallmark of cancer cells. We found that mouse models of myeloproliferative neoplasms (MPN) expressing mutant JAK2 displayed systemic metabolic changes including hypoglycemia and adipose atrophy. Modulation of nutrient availability modified MPN manifestations and survival. Hypoglycemia in MPN mice correlated with hyperactive erythropoiesis and was due to a combination of elevated glycolysis and increased oxidative phosphorylation. Transcriptomic and metabolomic analyses together with functional assays in hematopoietic stem and progenitor cells identified vulnerable metabolic nodes for therapeutic targeting. Inhibition of Pfkfb3, a key regulatory enzyme of glycolysis, increased blood glucose levels, improved blood counts and reduced splenomegaly. We observed additive efficacy with ruxolitinib. Mechanistically, altered redox homeostasis promoted apoptosis of susceptible MPN cells.

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Project 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.

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