Molecular Pathogenesis of Myeloproliferative Neoplasms

Rolles, Benjamin; Mullally, Ann

doi:10.1007/s11899-022-00685-1

Cited by 14 publications

(18 citation statements)

References 93 publications

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“…There are studies in mice where selective deletion of JAK2 in hepatocytes was shown to protect against steatosis and glucose intolerance induced by the intake of a high-fat diet [ 28 ], whereas patients with portal vein thrombosis associated with a point mutation in the JAK2 gene had a higher proportion of hepatocarcinoma [ 29 ]. Therefore, more studies are needed to clarify the role of changes in JAK2 signaling in pathophysiology, although numerous cases have been described that suggest that JAK2 mutations are related to carcinogenic processes [ 30 ].…”

Section: Regulation Of Leptin Efficiencymentioning

confidence: 99%

Recent Advances in the Knowledge of the Mechanisms of Leptin Physiology and Actions in Neurological and Metabolic Pathologies

Casado

Collado-Pérez

Frago

et al. 2023

IJMS

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Excess body weight is frequently associated with low-grade inflammation. Evidence indicates a relationship between obesity and cancer, as well as with other diseases, such as diabetes and non-alcoholic fatty liver disease, in which inflammation and the actions of various adipokines play a role in the pathological mechanisms involved in these disorders. Leptin is mainly produced by adipose tissue in proportion to fat stores, but it is also synthesized in other organs, where leptin receptors are expressed. This hormone performs numerous actions in the brain, mainly related to the control of energy homeostasis. It is also involved in neurogenesis and neuroprotection, and central leptin resistance is related to some neurological disorders, e.g., Parkinson’s and Alzheimer’s diseases. In peripheral tissues, leptin is implicated in the regulation of metabolism, as well as of bone density and muscle mass. All these actions can be affected by changes in leptin levels and the mechanisms associated with resistance to this hormone. This review will present recent advances in the molecular mechanisms of leptin action and their underlying roles in pathological situations, which may be of interest for revealing new approaches for the treatment of diseases where the actions of this adipokine might be compromised.

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Section: Regulation Of Leptin Efficiencymentioning

confidence: 99%

Recent Advances in the Knowledge of the Mechanisms of Leptin Physiology and Actions in Neurological and Metabolic Pathologies

Casado

Collado-Pérez

Frago

et al. 2023

IJMS

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“…Due to the clonal nature of MPNs, patients might experience transformation to another entity, or develop some types of leukemia, and rarely proceed to lymphoid malignancies [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Among the MPN entities, PMF (formerly known chronic idiopathic myelofibrosis) is the most complex and heterogeneous MPN entity both in terms of its clinical and biological characteristics and the distinctive criteria which consists of megakaryocyte hyperproliferation and bone marrow fibrosis [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…Subsequently, an overt fibrotic stage with marked fibrosis in the bone marrow occurs. The fibrotic stage of PMF is clinically characterized by leukoerythroblastosis in the blood, hepatomegaly, and splenomegaly [ 1 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…CALR mutations are found in about one fourth of PMF cases, and MPL mutations are found in less than 10% of cases. MPL and CALR also activate the JAK/STAT pathway [ 13 , 16 ]. In total, 10–15% of PMF cases are triple-negative for mutations in JAK2 , CALR , and MPL [ 13 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…MPL and CALR also activate the JAK/STAT pathway [ 13 , 16 ]. In total, 10–15% of PMF cases are triple-negative for mutations in JAK2 , CALR , and MPL [ 13 , 16 ]. Although these mutations are useful in distinguishing PMF from inflammatory conditions, they are not specific to PMF; mutations in these genes are found in essential thrombocythemia and polycythemia vera [ 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

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Use of Next Generation Sequencing to Define the Origin of Primary Myelofibrosis

Visani¹,

Etebari

Fuligni

et al. 2023

Cancers

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Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm (MPN) characterized by progressive bone marrow sclerosis, extra-medullary hematopoiesis, and possible transformation to acute leukemia. In the last decade, the molecular pathogenesis of the disease has been largely uncovered. Particularly, genetic and genomic studies have provided evidence of deregulated oncogenes in PMF as well as in other MPNs. However, the mechanisms through which transformation to either the myeloid or lymphoid blastic phase remain obscure. Particularly, it is still debated whether the disease has origins in a multi-potent hematopoietic stem cells or instead in a commissioned myeloid progenitor. In this study, we aimed to shed light upon this issue by using next generation sequencing (NGS) to study both myeloid and lymphoid cells as well as matched non-neoplastic DNA of PMF patients. Whole exome sequencing revealed that most somatic mutations were the same between myeloid and lymphoid cells, such findings being confirmed by Sanger sequencing. Particularly, we found 126/146 SNVs to be the e same (including JAK2V617F), indicating that most genetic events likely to contribute to disease pathogenesis occurred in a non-commissioned precursor. In contrast, only 9/27 InDels were similar, suggesting that this type of lesion contributed instead to disease progression, occurring at more differentiated stages, or maybe just represented “passenger” lesions, not contributing at all to disease pathogenesis. In conclusion, we showed for the first time that genetic lesions characteristic of PMF occur at an early stage of hematopoietic stem cell differentiation, this being in line with the possible transformation of the disease in either myeloid or lymphoid acute leukemia.

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Clonal dynamics and copy number variants by single‐cell analysis in leukemic evolution of myeloproliferative neoplasms

et al. 2023

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Transformation from chronic (CP) to blast phase (BP) in myeloproliferative neoplasm (MPN) remains poorly characterized, and no specific mutation pattern has been highlighted. BP‐MPN represents an unmet need, due to its refractoriness to treatment and dismal outcome. Taking advantage of the granularity provided by single‐cell sequencing (SCS), we analyzed paired samples of CP and BP in 10 patients to map clonal trajectories and interrogate target copy number variants (CNVs). Already at diagnosis, MPN present as oligoclonal diseases with varying ratio of mutated and wild‐type cells, including cases where normal hematopoiesis was entirely surmised by mutated clones. BP originated from increasing clonal complexity, either on top or independent of a driver mutation, through acquisition of novel mutations as well as accumulation of clones harboring multiple mutations, that were detected at CP by SCS but were missed by bulk sequencing. There were progressive copy‐number imbalances from CP to BP, that configured distinct clonal profiles and identified recurrences in genes including NF1, TET2, and BCOR, suggesting an additional level of complexity and contribution to leukemic transformation. EZH2 emerged as the gene most frequently affected by single nucleotide and CNVs, that might result in EZH2/PRC2‐mediated transcriptional deregulation, as supported by combined scATAC‐seq and snRNA‐seq analysis of the leukemic clone in a representative case. Overall, findings provided insights into the pathogenesis of MPN‐BP, identified CNVs as a hitherto poorly characterized mechanism and point to EZH2 dysregulation as target. Serial assessment of clonal dynamics might potentially allow early detection of impending disease transformation, with therapeutic implications.

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Molecular Pathogenesis of Myeloproliferative Neoplasms

Cited by 14 publications

References 93 publications

Recent Advances in the Knowledge of the Mechanisms of Leptin Physiology and Actions in Neurological and Metabolic Pathologies

Recent Advances in the Knowledge of the Mechanisms of Leptin Physiology and Actions in Neurological and Metabolic Pathologies

Use of Next Generation Sequencing to Define the Origin of Primary Myelofibrosis

Clonal dynamics and copy number variants by single‐cell analysis in leukemic evolution of myeloproliferative neoplasms

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