Recent insights regarding the molecular basis of myeloproliferative neoplasms

Jang, Minsoo; Choi, Chul Won

doi:10.3904/kjim.2019.317

Cited by 30 publications

(25 citation statements)

References 98 publications

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“…Irrespective of “driver” mutations, a hyper-activation of the JAK-STAT pathway is observed in all MF patients [ 5 ]. The molecular basis of TN remains mostly unknown, although a high molecular complexity has been previously described [ 6 ] and rare, alternative, somatic mutations in both JAK2 exon 14 and MPL exon 10 have been previously annotated [ 7 , 8 ]. TN MF is associated with an aggressive clinical behavior characterized by a higher risk of developing anemia and thrombocytopenia, poorer outcomes in comparison with patients affected by the other MF molecular subtypes and a high rate of leukemic transformation [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Distinct profile of CD34+ cells and plasma-derived extracellular vesicles from triple-negative patients with Myelofibrosis reveals potential markers of aggressive disease

Forte

Barone

Morsiani

et al. 2021

J Exp Clin Cancer Res

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Background Myelofibrosis (MF) is a clonal disorder of hemopoietic stem/progenitor cells (HSPCs) with high prevalence in elderly patients and mutations in three driver genes (JAK2, MPL, or CALR). Around 10–15% of patients are triple-negative (TN) for the three driver mutations and display significantly worse survival. Circulating extracellular vesicles (EVs) play a role in intercellular signaling and are increased in inflammation and cancer. To identify a biomolecular signature of TN patients, we comparatively evaluated the circulating HSPCs and their functional interplay with the microenvironment focusing on EV analysis. Methods Peripheral blood was collected from MF patients (n = 29; JAK2V617F mutation, n = 23; TN, n = 6) and healthy donors (HD, n = 10). Immunomagnetically isolated CD34+ cells were characterized by gene expression profiling analysis (GEP), survival, migration, and clonogenic ability. EVs were purified from platelet-poor plasma by ultracentrifugation, quantified using the Nanosight technology and phenotypically characterized by flow cytometry together with microRNA expression. Migration and survival of CD34+ cells from patients were also analyzed after in vitro treatments with selected inflammatory factors, i.e. (Interleukin (IL)-1β, Tumor Necrosis Factor (TNF)-α, IL6) or after co-culture with EVs from MF patients/HD. Results The absolute numbers of circulating CD34+ cells were massively increased in TN patients. We found that TN CD34+ cells show in vitro defective functions and are unresponsive to the inflammatory microenvironment. Of note, the plasma levels of crucial inflammatory cytokines are mostly within the normal range in TN patients. Compared to JAK2V617F-mutated patients, the GEP of TN CD34+ cells revealed distinct signatures in key pathways such as survival, cell adhesion, and inflammation. Importantly, we observed the presence of mitochondrial components within plasma EVs and a distinct phenotype in TN-derived EVs compared to the JAK2V617F-mutated MF patients and HD counterparts. Notably, TN EVs promoted the survival of TN CD34+ cells. Along with a specific microRNA signature, the circulating EVs from TN patients are enriched with miR-361-5p. Conclusions Distinct EV-driven signals from the microenvironment are capable to promote the TN malignant hemopoiesis and their further investigation paves the way toward novel therapeutic approaches for rare MF.

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Section: Introductionmentioning

confidence: 99%

Distinct profile of CD34+ cells and plasma-derived extracellular vesicles from triple-negative patients with Myelofibrosis reveals potential markers of aggressive disease

Forte

Barone

Morsiani

et al. 2021

J Exp Clin Cancer Res

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“…Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-negative MPNs) arise from a single clonal hematopoietic stem cell (HSC) leading to proliferation of more than one cell lineage, with transitional forms from one entity to another. Over 95% of PV, ET, and PMF are associated with mutually exclusive somatic driver mutations JAK2 V617F, calreticulin ( CALR ), and myeloproliferative leukemia protein ( MPL ) [ 9 , 10 , 11 , 12 , 13 ]. Acquisition of somatic driver mutations leads to the development of the MPN stem cells.…”

Section: Introductionmentioning

confidence: 99%

“…This is characterized by survival advantage of MPN stem cells over normal HSCs that is sustained by a dysregulated bone marrow niche via a positive feedback mechanism [ 9 , 14 ] ( Figure 1 ). Further acquisition of non-driver mutations then plays a pivotal role in determining disease phenotype and promoting leukemic progression [ 9 , 10 , 13 ] ( Figure 2 ). At diagnosis, all CML patients harbor abnormal HSCs [ 8 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

Yung

Lee

Chu

et al. 2021

IJMS

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Myeloproliferative neoplasms (MPNs) are unique hematopoietic stem cell disorders sharing mutations that constitutively activate the signal-transduction pathways involved in haematopoiesis. They are characterized by stem cell-derived clonal myeloproliferation. The key MPNs comprise chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). CML is defined by the presence of the Philadelphia (Ph) chromosome and BCR-ABL1 fusion gene. Despite effective cytoreductive agents and targeted therapy, complete CML/MPN stem cell eradication is rarely achieved. In this review article, we discuss the novel agents and combination therapy that can potentially abnormal hematopoietic stem cells in CML and MPNs and the CML/MPN stem cell-sustaining bone marrow microenvironment.

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“…CALR mutations are the second most common mutation in MPNs, and are found in 20% to 25% of ET and 25% to 30% of PMF patients. MPL mutations are found in 3% of ET patients and 5% of PMF patients [3]. Patients without mutations in any of these driver genes can be diagnosed with ET or PMF when their clinical and hematologic features meet speci c criteria, including clonal mutations in any of the following genes: ASXL1, EZH2, TET2, IDH1/2, SRSF2, and SF3B1 [1].…”

Section: Introductionmentioning

confidence: 99%

Impact of integrated genetic information on diagnosis and prognostication for myeloproliferative neoplasms in the next-generation sequencing era

Lee

Eom

et al. 2020

Preprint

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Background: Since next-generation sequencing has been widely used in clinical laboratory, diagnosis and risk stratification of hematologic malignancies are greatly dependent on genetic aberrations. Methods: In this study, we analyzed the genomic landscape of 200 patients with myeloproliferative neoplasms (MPNs) using targeted panel sequencing covering including 86 genes. Conventional BM karyotyping was also performed to determine chromosomal aberration. We analyzed relationships between genetic profiles and clinical outcomes including acute transformation, bone marrow fibrosis and death.Results: Mutations in JAK2, CALR, and MPL were detected in 76.4% of MPNs. The proportion of patients with clonal genetic markers increased up to 86.4% when all detectable genetic aberrations were included. Significant co-occurring genetic aberrations potentially associated with phenotype and/or disease progression, including those in JAK2/SF3B1 (P=0.017) and TP53/del(13q), del(5q), -7/del(7q) and complex karyotypes (P=0.038, P<0.001, P<0.001 and P<0.001, respectively) were detected. We also identified genetic aberrations associated with patient outcomes: TP53 and -7/del(7q) for inferior survival (HR, 95% CI: 64.2, 3.8-1096.5, P=0.0041, HR, 95% CI: 14.0, 1.5-132.7, P=0.0219), RUNX1, TP53 and IDH1/2 for leukemic transformation (HR, 95% CI: 68.1, 3.6-1300.4, P=0.005, HR, 95% CI: 16.3, 1.2-222.7, P=0.0364, HR, 95% CI: 32.5, 2.8-371.1, P=0.0051), SF2B1, IDH1/2, ASXL1 and del(20q) for fibrotic progression (HR, 95% CI: 31.5, 4.1-243.3, P=0.0009, HR, 95% CI: 21.2, 3.4-132.2, P=0.0011, HR, 95% CI: 4.3, 1.1-16.4, P=0.0358, HR, 95% CI: 44.5, 6.1-323.0, P=0.0002). We compared risk stratification systems and found that mutation-enhanced prognostic scoring systems could identify lower risk polycythemia vera and essential thrombocythemia and higher risk primary myelofibrosis (P<0.001, P<0.001 and P<0.001, respectively). Furthermore, the new risk stratification systems showed better predictive capacity of patient outcome. Conclusions: These results collectively indicate that integrated genetic information can enhance diagnosis and prognostication in patients with myeloproliferative neoplasms.

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Recent insights regarding the molecular basis of myeloproliferative neoplasms

Cited by 30 publications

References 98 publications

Distinct profile of CD34+ cells and plasma-derived extracellular vesicles from triple-negative patients with Myelofibrosis reveals potential markers of aggressive disease

Distinct profile of CD34+ cells and plasma-derived extracellular vesicles from triple-negative patients with Myelofibrosis reveals potential markers of aggressive disease

Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

Impact of integrated genetic information on diagnosis and prognostication for myeloproliferative neoplasms in the next-generation sequencing era

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