Genetic lesions disrupting calreticulin 3′‐untranslated region in <scp>JAK2</scp> mutation‐negative polycythemia <scp>vera</scp>

Quattrocchi, Alberto; Maiorca, Carlo; Billi, Monia; Tomassini, Simona; Marinis, Elisabetta De; Cenfra, Natalia; Equitani, Francesco; Gentile, M.; Ceccherelli, Alessia; Banella, Cristina; Mecarocci, Sergio; Scerpa, Maria Cristina; Pisanò, Stefania; Pacilli, Annalisa; Cristofano, Claudio Di; Mancini, Massimiliano; Guglielmelli, Paola; Vannucchi, Alessandro M.; Noguera, Nélida I.; Grignani, Francesco; Cimino, Giuseppe; Nervi, Clara

doi:10.1002/ajh.25911

Cited by 9 publications

(6 citation statements)

References 7 publications

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“…Two women and three men affected by NLSD-M, from the Italian NLSD Group [ 9 ], aged 50 y and 68 y, underwent skin biopsy after informed consent was provided. Clinical and genetic data of these patients are briefly summarized in Table 1 .…”

Section: Methodsmentioning

confidence: 99%

Effects of Triheptanoin on Mitochondrial Respiration and Glycolysis in Cultured Fibroblasts from Neutral Lipid Storage Disease Type M (NLSD-M) Patients

et al. 2023

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Neutral lipid storage disease type M (NLSD-M) is an ultra-rare, autosomal recessive disorder that causes severe skeletal and cardiac muscle damage and lipid accumulation in all body tissues. In this hereditary pathology, the defective action of the adipose triglyceride lipase (ATGL) enzyme induces the enlargement of cytoplasmic lipid droplets and reduction in the detachment of mono- (MG) and diglycerides (DG). Although the pathogenesis of muscle fiber necrosis is unknown, some studies have shown alterations in cellular energy production, probably because MG and DG, the substrates of Krebs cycle, are less available. No tests have been tried with medium-chain fatty acid molecules to evaluate the anaplerotic effect in NLSD cells. In this study, we evaluated the in vitro effect of triheptanoin (Dojolvi®), a highly purified chemical triglyceride with seven carbon atoms, in fibroblasts obtained from five NLSD-M patients. Glycolytic and mitochondrial functions were determined by Seahorse XF Agylent Technology, and cellular viability and triglyceride content were measured through colorimetric assays. After the addition of triheptanoin, we observed an increase in glycolysis and mitochondrial respiration in all patients compared with healthy controls. These preliminary results show that triheptanoin is able to induce an anaplerotic effect in NLSD-M fibroblasts, paving the way towards new therapeutic strategies.

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Section: Methodsmentioning

confidence: 99%

Effects of Triheptanoin on Mitochondrial Respiration and Glycolysis in Cultured Fibroblasts from Neutral Lipid Storage Disease Type M (NLSD-M) Patients

et al. 2023

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“…Two mutations of the more than 50 reported variants-a 52 base pair deletion (type 1) and a 5 base pair insertion (type 2)-accounted for 80-90% of the mutations [36,37]. The CALR mutations were found in 60-80% of ET and PMF patients without JAK2 and MPL mutations and could also be identified in rare cases of PV and RARS-T [38][39][40][41]. Despite the multitude of CALR mutations, they all shared the unique characteristics that they result in a +1 base-pair frameshift of the entire downstream coding sequence leading to a a collection of negatively charged amino acids being replaced with a positively charged chain [36,37].…”

Section: Discovery Of Phenotypic Driver Mutations In Myeloproliferatimentioning

confidence: 96%

Clonal Hematopoiesis and Mutations of Myeloproliferative Neoplasms

Kjær

2020

Cancers

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Myeloproliferative neoplasms (MPNs) are associated with the fewest number of mutations among known cancers. The mutations propelling these malignancies are phenotypic drivers providing an important implement for diagnosis, treatment response monitoring, and gaining insight into the disease biology. The phenotypic drivers of Philadelphia chromosome negative MPN include mutations in JAK2, CALR, and MPL. The most prevalent driver mutation JAK2V617F can cause disease entities such as essential thrombocythemia (ET) and polycythemia vera (PV). The divergent development is considered to be influenced by the acquisition order of the phenotypic driver mutation relative to other MPN-related mutations such as TET2 and DNMT3A. Advances in molecular biology revealed emergence of clonal hematopoiesis (CH) to be inevitable with aging and associated with risk factors beyond the development of blood cancers. In addition to its well-established role in thrombosis, the JAK2V617F mutation is particularly connected to the risk of developing cardiovascular disease (CVD), a pertinent issue, as deep molecular screening has revealed the prevalence of the mutation to be much higher in the background population than previously anticipated. Recent findings suggest a profound under-diagnosis of MPNs, and considering the impact of CVD on society, this calls for early detection of phenotypic driver mutations and clinical intervention.

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“…Mitochondrial and glycolytic functions were assessed using a Seahorse Bioscience XFe96 analyzer in combination with the Seahorse Bioscience XF Cell Mito Stress Test and the Bioscience XF Cell Glycolysis Stress Test (Agilent Technologies, Santa Clara, CA, USA), respectively, as described [44]. Briefly, the extracellular acidification rate (ECAR), reflecting the conversion of glucose to lactate and resulting in a net production of protons in the extracellular medium, was measured directly using the Agilent Seahorse XF instrument.…”

Section: Metabolic Assaysmentioning

confidence: 99%

Ascorbate Plus Buformin in AML: A Metabolic Targeted Treatment

Banella

Catalano

Travaglini

et al. 2022

Cancers

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In the present study, we characterized the metabolic background of different Acute Myeloid Leukemias’ (AMLs) cells and described a heterogeneous and highly flexible energetic metabolism. Using the Seahorse XF Agilent, we compared the metabolism of normal hematopoietic progenitors with that of primary AML blasts and five different AML cell lines. We assessed the efficacy and mechanism of action of the association of high doses of ascorbate, a powerful oxidant, with the metabolic inhibitor buformin, which inhibits mitochondrial complex I and completely shuts down mitochondrial contributions in ATP production. Primary blasts from seventeen AML patients, assayed for annexin V and live/dead exclusion by flow cytometry, showed an increase in the apoptotic effect using the drug combination, as compared with ascorbate alone. We show that ascorbate inhibits glycolysis through interfering with HK1/2 and GLUT1 functions in hematopoietic cells. Ascorbate combined with buformin decreases mitochondrial respiration and ATP production and downregulates glycolysis, enhancing the apoptotic effect of ascorbate in primary blasts from AMLs and sparing normal CD34+ bone marrow progenitors. In conclusion, our data have therapeutic implications especially in fragile patients since both agents have an excellent safety profile, and the data also support the clinical evaluation of ascorbate–buformin in association with different mechanism drugs for the treatment of refractory/relapsing AML patients with no other therapeutic options.

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Genetic lesions disrupting calreticulin 3′‐untranslated region in JAK2 mutation‐negative polycythemia vera

Cited by 9 publications

References 7 publications

Effects of Triheptanoin on Mitochondrial Respiration and Glycolysis in Cultured Fibroblasts from Neutral Lipid Storage Disease Type M (NLSD-M) Patients

Effects of Triheptanoin on Mitochondrial Respiration and Glycolysis in Cultured Fibroblasts from Neutral Lipid Storage Disease Type M (NLSD-M) Patients

Clonal Hematopoiesis and Mutations of Myeloproliferative Neoplasms

Ascorbate Plus Buformin in AML: A Metabolic Targeted Treatment

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