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N-acetyl-D-glucosamine is an oncometabolite modulating mast cell effector functions by chromatin remodeling

ABSTRACT: We investigated the metabolic regulation of mast cell (MC) functions to control them. MCs are sentinels of the immune system with functions involved not only in host defense but also, if not properly controlled, in MC disorders such as systemic mastocytosis (SM). We identified N-acetyl-D-glucosamine (GlcNAc or NAG) as both a circulating biomarker for SM severity and an oncometabolite that promotes uncontrolled degranulation and proliferation of MCs expressing the Kit kinase domain mutant allele, D816V, that is both an oncogene and characterizes patients with SM. Given the known role of GlcNAc-related protein glycosylation in modifying factors involved in epigenetic regulation of gene expression and the effects of GlcNAc on neoplastic MCs effector functions, we asked whether the increased susceptibility of KIT D816V MCs to GlcNAc was due to chromatin state changes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149106 | GEO | 2023/04/20

REPOSITORIES: GEO

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Targeting Sphingosine Kinase Isoforms Effectively Reduces Growth and Survival of Neoplastic Mast Cells with D816V-KIT

Project description:Mastocytosis is a disorder resulting from an abnormal mast cell (MC) accumulation in tissues that is often associated with the D816V mutation in KIT, the tyrosine kinase receptor for stem cell factor. Therapies available to treat aggressive presentations of mastocytosis are limited, thus exploration of novel pharmacological targets that reduce MC burden is desirable. Since increased generation of the lipid mediator sphingosine-1-phosphate (S1P) by sphingosine kinase (SPHK) has been linked to oncogenesis, we studied the involvement of the two SPHK isoforms (SPHK1 and SPHK2) in the regulation of neoplastic human MC growth. While SPHK2 inhibition prevented entry into the cell cycle in normal and neoplastic human MCs with minimal effect on cell survival, SPHK1 inhibition caused cell cycle arrest in G2/M and apoptosis, particularly in D816V-KIT MCs. This was mediated via activation of the DNA damage response cascade, including phosphorylation of the checkpoint kinase 2 (CHK2), CHK2-mediated CDC25c depletion and p53 activation. Combination treatment of SPHK inhibitors with KIT inhibitors showed greater growth inhibition of D816V-KIT MCs than either inhibitor alone. Furthermore, inhibition of SPHK reduced the number of malignant bone marrow MCs from patients with mastocytosis and the growth of D816V-KIT MCs in a xenograft mouse model. Our results reveal a role for SPHK isoforms in the regulation of growth and survival in normal and neoplastic MCs and suggest a regulatory function for SPHK1 in the DNA damage response in MCs with KIT mutations. The findings also suggest that targeting the SPHK/S1P axis may provide an alternative to tyrosine kinase inhibitors, alone or in combination, for treatment of aggressive mastocytosis and other hematological malignancies associated with the D816V-KIT mutation.

2018-03-30 | GSE111060 | GEO

KIT D816V mast cells derived from induced pluripotent stem cells recapitulate systemic mastocytosis transcriptional profile

Project description:Mast cells (MC) represent a population of hematopoietic cells with a key role in innate and adaptive immunity and are well known for their detrimental role in allergic responses. Yet, MC occur in low abundance which hampers their detailed molecular analysis. Here, we capitalized on the potential of induced pluripotent stem (iPS) cells to give rise to all cells of the body and established a robust protocol for human iPS cell differentiation towards MC. Relying on a panel of systemic mastocytosis (SM) patient-specific iPS cell lines carrying the KIT D816V mutation, we generated functional MC that recapitulate SM disease features: increased number of MC, abnormal maturation kinetics and activated phenotype, CD2 and CD30 surface expression and a transcriptional signature characterized by upregulated expression of innate and inflammatory response genes. Therefore, human iPS cell-derived MC are a reliable and close-to-human tool for disease modeling and pharmacological screening to explore novel MC therapeutics.

2023-04-05 | GSE223883 | GEO

The association of Greig cephalopolysyndactyly syndrome and congenital mastocytosis reveals the hedgehog signaling pathway involvement in mastocytosis development

Project description:Mastocytosis is a heterogeneous disease characterized by an abnormal accumulation of mast cells (MCs) in one or several organs.Although a somatic KIT D816V mutation is detected in ~85% of patients, attempts to demonstrate its oncogenic effect alone have repeatedly failed, suggesting that additional pathways are involved in MC transformation. From three children presenting with both Greig cephalopolysyndactyly syndrome (GCPS, MIM#175700) and congenital mastocytosis, we demonstrated the involvement of the hedgehog (Hh) pathway in mastocytosis. GCPS is an extremely rare syndrome resulting from haploinsufficiency of GLI3, the major repressor of Hh family members. From these familial cases of mastocytosis, we demonstrate that the Hh pathway is barely active in normal primary MCs and overactive in neoplastic MCs and that GLI3 and KITmutations have a synergistic, tumorigenic effect on the onset of mastocytosis in a GCPS mouse model. Finally, we show that Hh inhibitors suppress neoplastic MC proliferation in vitro and extend the survival time of ASM mice. This work revealed, for the first time, the involvement of Hh signaling in the pathophysiology of mastocytosis and demonstrated the cooperative effects of the KIT and Hh oncogenic pathways in ASM, leading to the identification of new promising therapeutic targets.

2021-12-02 | E-MTAB-9893 | biostudies-arrayexpress

Role of adhesion receptors in mast cell disease-evolution

Project description:Systemic mastocytosis (SM) is an incurable neoplasm characterized by abnormal accumulation of neoplastic mast cells (MC) in vascularized organs. In indolent SM, MC express several different adhesion-molecules including CD2 and CD58, and form focal tissue-aggregates, whereas in advanced SM, MC often lack CD2 and produce a more diffuse infiltration-pattern. To explore the functional role of CD2 in the pathology of SM, stable CD2+ and CD2− subclones of the human MC-leukemia cell line HMC-1 were generated and injected intraperitoneally into pfp/rag2 mice. CD2+ HMC-1 cells formed solid mastocytomas in the peritoneum and lungs, whereas CD2− cells produced diffuse infiltration. CD2+ and CD2− HMC-1 subclones all displayed the driver-mutant KIT D816V, exhibited the same growth-kinetics, and displayed identical adhesion-receptors including CD44 and selectin-ligands. To explore the mechanism of organ invasion, E- and P-selectin-deficient scid mice (scid-select) were employed. While massive HMC-1 infiltrates were detected in the lungs of control mice, infiltration was markedly reduced or absent in scid-select mice. The invasion-receptor CD44 was detectable in all MC infiltrates, with most abundant expression in the invasion-front. Together, our data show that selectins mediate organ-invasion of MC and CD2-CD58 interactions contribute to a more focal infiltration-pattern which is lost during progression to MC leukemia.

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Role of adhesion receptors in mast cell disease-evolution

2013-01-01 | E-GEOD-33504 | biostudies-arrayexpress

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2021-11-25 | PXD023851 | Pride

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