Browse
Submit Data
Databases
API
Help

Dataset Information

24 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms.

ABSTRACT: Increased energy requirement and metabolic reprogramming are hallmarks of cancer cells. We show that metabolic alterations in hematopoietic cells are fundamental to the pathogenesis of mutant JAK2-driven myeloproliferative neoplasms (MPNs). We found that expression of mutant JAK2 augmented and subverted metabolic activity of MPN cells, resulting in systemic metabolic changes in vivo, including hypoglycemia, adipose tissue atrophy, and early mortality. Hypoglycemia in MPN mouse models correlated with hyperactive erythropoiesis and was due to a combination of elevated glycolysis and increased oxidative phosphorylation. Modulating nutrient supply through high-fat diet improved survival, whereas high-glucose diet augmented the MPN phenotype. Transcriptomic and metabolomic analyses identified numerous metabolic nodes in JAK2-mutant hematopoietic stem and progenitor cells that were altered in comparison with wild-type controls. We studied the consequences of elevated levels of Pfkfb3, a key regulatory enzyme of glycolysis, and found that pharmacological inhibition of Pfkfb3 with the small molecule 3PO reversed hypoglycemia and reduced hematopoietic manifestations of MPNs. These effects were additive with the JAK1/2 inhibitor ruxolitinib in vivo and in vitro. Inhibition of glycolysis by 3PO altered the redox homeostasis, leading to accumulation of reactive oxygen species and augmented apoptosis rate. Our findings reveal the contribution of metabolic alterations to the pathogenesis of MPNs and suggest that metabolic dependencies of mutant cells represent vulnerabilities that can be targeted for treating MPNs.

SUBMITTER: Rao TN

PROVIDER: S-EPMC6872961 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

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.

2019-11-29 | GSE116571 | GEO

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

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

| PRJNA479424 | ENA

Myeloproliferative neoplasms can be initiated from a single hematopoietic stem cell expressing JAK2-V617F.

Project description:The majority of patients with myeloproliferative neoplasms (MPNs) carry a somatic JAK2-V617F mutation. Because additional mutations can precede JAK2-V617F, it is questioned whether JAK2-V617F alone can initiate MPN. Several mouse models have demonstrated that JAK2-V617F can cause MPN; however, in all these models disease was polyclonal. Conversely, cancer initiates at the single cell level, but attempts to recapitulate single-cell disease initiation in mice have thus far failed. We demonstrate by limiting dilution and single-cell transplantations that MPN disease, manifesting either as erythrocytosis or thrombocytosis, can be initiated clonally from a single cell carrying JAK2-V617F. However, only a subset of mice reconstituted from single hematopoietic stem cells (HSCs) displayed MPN phenotype. Expression of JAK2-V617F in HSCs promoted cell division and increased DNA damage. Higher JAK2-V617F expression correlated with a short-term HSC signature and increased myeloid bias in single-cell gene expression analyses. Lower JAK2-V617F expression in progenitor and stem cells was associated with the capacity to stably engraft in secondary recipients. Furthermore, long-term repopulating capacity was also present in a compartment with intermediate expression levels of lineage markers. Our studies demonstrate that MPN can be initiated from a single HSC and illustrate that JAK2-V617F has complex effects on HSC biology.

| S-EPMC4203945 | biostudies-literature

Exploitation of the neural-hematopoietic stem cell niche axis to treat myeloproliferative neoplasms.

Project description: Not available

| S-EPMC6442959 | biostudies-literature

Therapy with JAK2 inhibitors for myeloproliferative neoplasms.

Project description:The development of JAK2 inhibitors followed the discovery of activating mutation of JAK2 (JAK2V617F) in patients with classic Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPN). It is now known that mutations activating the JAK-STAT pathway are ubiquitous in Ph-negative MPN, and that the deregulated JAK-STAT pathway plays a central role in the pathogenesis of these disorders. JAK2 inhibitors thus are effective in patients both with and without the JAK2V617F mutation. This article reviews the rationale for using JAK2 inhibitors in Ph-negative MPN, and the results of more recent clinical trials with these drugs.

| S-EPMC4406395 | biostudies-literature

JAK2 in Myeloproliferative Neoplasms: Still a Protagonist.

Project description:The discovery of the activating V617F mutation in Janus kinase 2 (JAK2) has been decisive for the understanding of myeloproliferative neoplasms (MPN). Activated JAK2 signaling by JAK2, CALR, and MPL mutations has become a focus for the development of targeted therapies for patients with MPN. JAK2 inhibitors now represent a standard of clinical care for certain forms of MPN and offer important benefits for MPN patients. However, several key aspects remain unsolved regarding the targeted therapy of MPN with JAK2 inhibitors, such as reducing the MPN clone and how to avoid or overcome a loss of response. Here, we summarize the current knowledge on the structure and signaling of JAK2 as central elements of MPN pathogenesis and feature benefits and limitations of therapeutic JAK2 targeting in MPN.

| S-EPMC8874480 | biostudies-literature

JAK2/IDH-mutant-driven myeloproliferative neoplasm is sensitive to combined targeted inhibition.

Project description:Patients with myeloproliferative neoplasms (MPNs) frequently progress to bone marrow failure or acute myeloid leukemia (AML), and mutations in epigenetic regulators such as the metabolic enzyme isocitrate dehydrogenase (IDH) are associated with poor outcomes. Here, we showed that combined expression of Jak2V617F and mutant IDH1R132H or Idh2R140Q induces MPN progression, alters stem/progenitor cell function, and impairs differentiation in mice. Jak2V617F Idh2R140Q-mutant MPNs were sensitive to small-molecule inhibition of IDH. Combined inhibition of JAK2 and IDH2 normalized the stem and progenitor cell compartments in the murine model and reduced disease burden to a greater extent than was seen with JAK inhibition alone. In addition, combined JAK2 and IDH2 inhibitor treatment also reversed aberrant gene expression in MPN stem cells and reversed the metabolite perturbations induced by concurrent JAK2 and IDH2 mutations. Combined JAK2 and IDH2 inhibitor therapy also showed cooperative efficacy in cells from MPN patients with both JAK2mut and IDH2mut mutations. Taken together, these data suggest that combined JAK and IDH inhibition may offer a therapeutic advantage in this high-risk MPN subtype.

| S-EPMC5785272 | biostudies-literature

JAK2 inhibitors for myeloproliferative neoplasms: what is next?

Project description:Since its approval in 2011, the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib has evolved to become the centerpiece of therapy for myelofibrosis (MF), and its use in patients with hydroxyurea resistant or intolerant polycythemia vera (PV) is steadily increasing. Several other JAK2 inhibitors have entered clinical testing, but none have been approved and many have been discontinued. Importantly, the activity of these agents is not restricted to patients with JAK2 V617F or exon 12 mutations. Although JAK2 inhibitors provide substantial clinical benefit, their disease-modifying activity is limited, and rational combinations with other targeted agents are needed, particularly in MF, in which survival is short. Many such combinations are being explored, as are other novel agents, some of which could successfully be combined with JAK2 inhibitors in the future. In addition, new JAK2 inhibitors with the potential for less myelosuppression continue to be investigated. Given the proven safety and efficacy of ruxolitinib, it is likely that ruxolitinib-based combinations will be a major way forward in drug development for MF. If approved, less myelosuppressive JAK2 inhibitors such as pacritinib or NS-018 could prove to be very useful additions to the therapeutic armamentarium in MF. In PV, inhibitors of histone deacetylases and human double minute 2 have activity, but their role, if any, in the future treatment algorithm is uncertain, given the availability of ruxolitinib and renewed interest in interferons. Ruxolitinib is in late-phase clinical trials in essential thrombocythemia, in which it could fill an important void for patients with troublesome symptoms.

| S-EPMC5510786 | biostudies-literature

Prospect of JAK2 inhibitor therapy in myeloproliferative neoplasms.

Project description:The discovery of the Janus kinase (JAK)2 V617F mutation in patients with myeloproliferative neoplasms was a major milestone in understanding the biology of those disorders. Several groups simultaneously reported on the high incidence of this mutation in patients with myeloproliferative neoplasms: almost all patients with polycythemia vera harbor the mutation and about 50% of patients with essential thrombocythemia and primary myelofibrosis have the mutation, making the development of JAK2 tyrosine kinase inhibitors an attractive therapeutic goal. In addition, inhibition of JAK2 kinase may have a therapeutic role in other hematologic malignancies, such as chronic myeloid leukemia or lymphoma. A number of molecules that inhibit JAK2 kinase have been described in the literature, and several are being evaluated in a clinical setting. Here, we summarize current clinical experience with JAK2 inhibitors.

| S-EPMC5176249 | biostudies-literature

Targeted therapies for myeloproliferative neoplasms.

Project description:The discovery of JAK2V617F and the demonstration that BCR-ABL-negative myeloproliferative neoplasms (MPNs) are driven by abnormal JAK2 activation have led to advances in diagnostic algorithms, prognosis and ultimately also treatment strategies. The JAK 1/2 inhibitor ruxolitinib was a pivotal moment in the treatment of MPNs, representing the first targeted treatment in this field. Despite a weak effect on the cause of the disease itself in MPNs, ruxolitinib improves the clinical state of patients and increases survival in myelofibrosis. In parallel, other JAK inhibitors with potential for pathologic and molecular remissions, less myelosuppression, and with greater selectivity for JAK1 or JAK2, and the ability to overcome JAK inhibitor persistence are in various stages of development. Moreover, many novel classes of targeted agents continue to be investigated in efforts to build on the progress made with ruxolitinib. This article will discuss some of the advances in the targeted therapy in this field in recent years and explore in greater detail some of the most advanced emerging agents as well as those with greatest potential.

| S-EPMC6636147 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data