Co-existence of mutations in myeloproliferative neoplasms and their clinical significance: a prognostic approach

Hadad, Elham Homaei; Pezeshki, Seyed Mohammad Sadegh; Shahrabi, Saeid; Malehi, Amal Saki; Saki, Najmaldin

doi:10.1080/17474086.2020.1819232

Cited by 3 publications

(6 citation statements)

References 62 publications

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“…Even in our small collective, the co-existence of different mutations (cumulation of mutations) appeared to be prognostically unfavorable, as described elsewhere (e.g., [ 1 ] and [ 5 ]). We could show that progressed patients from our collective had an increased number of mutations already in the first biopsy compared to the control collective.…”

Section: Discussionsupporting

confidence: 61%

“…The term myeloproliferative neoplasm (MPN) subsumes a group of hematopoietic stem cell disorders that are all characterized by clonal expansion of one or more myeloid lineages. With the discovery of distinct driver mutations in MPN, molecular analyses have gained immense importance in terms of diagnosis, follow-up and prognosis [ 1 ]. In BCR - ABL1 -negative MPN, one of the canonical driver mutations, i.e., JAK2 , CALR , MPL or—in cases of CNL— CSF3R , can be found in more than 90% of cases, these mutations mostly being mutually exclusive [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…All these mutations directly or indirectly activate the JAK/STAT signaling pathway of the neoplastic clone [ 3 , 4 ]. Regardless of these known drivers, the acquisition of additional somatic mutations in MPN contributes to altered gene expression and is associated with a poorer prognosis, making the number of driver-independent somatic mutations one of the strongest predictors of outcome [ 1 , 3 , 5 ]. Moreover, not only the sum of mutations, but also the sequence, in which they are gained (i.e., before or after the actual driver mutation), influences the phenotype, subclonal plasticity and drug sensitivity and therefore might be of relevance for the individual patient [ 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

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Molecular Progression of Myeloproliferative and Myelodysplastic/Myeloproliferative Neoplasms: A Study on Sequential Bone Marrow Biopsies

Brune

Rau

Overkamp

et al. 2021

Cancers

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Myeloproliferative neoplasms (MPN) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) both harbor the potential to undergo myelodysplastic progression or acceleration and can transform into blast-phase MPN or MDS/MPN, a form of secondary acute myeloid leukemia (AML). Although the initiating transforming events are yet to be determined, current concepts suggest a stepwise acquisition of (additional) somatic mutations—apart from the initial driver mutations—that trigger disease evolution. In this study we molecularly analyzed paired bone marrow samples of MPN and MDS/MPN patients with known progression and compared them to a control cohort of patients with stable disease course. Cases with progression displayed from the very beginning a higher number of mutations compared to stable ones, of which mutations in five (ASXL1, DNMT3A, NRAS, SRSF2 and TP53) strongly correlated with progression and/or transformation, even if only one of these genes was mutated, and this particularly applied to MPN. TET2 mutations were found to have a higher allelic frequency than the putative driver mutation in three progressing cases (“TET2-first”), whereas two stable cases displayed a TET2-positive subclone (“TET2-second”), supporting the hypothesis that not only the sum of mutations but also their order of appearance matters in the course of disease. Our data emphasize the importance of genetic testing in MPN and MDS/MPN patients in terms of risk stratification and identification of imminent disease progression.

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Section: Discussionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular Progression of Myeloproliferative and Myelodysplastic/Myeloproliferative Neoplasms: A Study on Sequential Bone Marrow Biopsies

Brune

Rau

Overkamp

et al. 2021

Cancers

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“…All of these mutations either directly or indirectly stimulate the JAK/STAT signaling pathway in the neoplastic clone, providing an advantage over the background hematopoiesis [5,6]. Importantly, the number of "non-driver" somatic mutations is one of the best prognostic indicators in MPN, suggesting they additively increase the fitness of the clone [5,7,8]. Moreover, the order in which "nondriver" mutations occur (i.e., before or after the driver mutation) affects the phenotype, subclonal plasticity, and treatment sensitivity and may therefore be relevant for a given patient too [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Progression in Myeloid Neoplasms: Beyond the Myeloblast

Faria

Tzankov

2023

Pathobiology

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Disease progression in myelodysplastic syndromes (MDS), myelodysplastic-myeloproliferative neoplasms (MDS/MPN), and myeloproliferative neoplasms (MPN), altogether referred to as myeloid neoplasms (MN), is a major source of mortality. Apart from transformation to acute myeloid leukemia, the clinical progression of MN is mostly due to the overgrowth of pre-existing hematopoiesis by the MN without an additional transforming event. Still, MN may evolve along other recurrent yet less well-known scenarios: (1) acquisition of MPN features in MDS or (2) MDS features in MPN, (3) progressive myelofibrosis (MF), (4) acquisition of chronic myelomonocytic leukemia (CMML)-like characteristics in MPN or MDS, (5) development of myeloid sarcoma (MS), (6) lymphoblastic (LB) transformation, (7) histiocytic/dendritic outgrowths. These MN-transformation types exhibit a propensity for extramedullary sites (e.g., skin, lymph nodes, liver), highlighting the importance of lesional biopsies in diagnosis. Gain of distinct mutations/mutational patterns seems to be causative or at least accompanying several of the above-mentioned scenarios. MDS developing MPN features often acquire MPN driver mutations (usually JAK2), and MF. Conversely, MPN gaining MDS features develop, e.g., ASXL1, IDH1/2, SF3B1, and/or SRSF2 mutations. Mutations of RAS-genes are often detected in CMML-like MPN progression. MS ex MN is characterized by complex karyotypes, FLT3 and/or NPM1 mutations, and often monoblastic phenotype. MN with LB transformation is associated with secondary genetic events linked to lineage reprogramming leading to the deregulation of ETV6, IKZF1, PAX5, PU.1, and RUNX1. Finally, the acquisition of MAPK-pathway gene mutations may shape MN toward histiocytic differentiation. Awareness of all these less well-known MN-progression types is important to guide optimal individual patient management.

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“…Almost one third of the patients with MPNs harbor non-driver molecular lesions that might cooperate with the driver mutations in fostering disease progression [18,19]. The genes involved are those relevant to epigenetic (e.g., TET2, ASXL1, IDH1, IDH2, DNMT3A, EZH2), RNA splicing (e.g., SF3B1, SRSF2, U2AF1) or transcriptional (e.g., IKZF1, TP53, NF-E2, CUX1) regulation, some of which carry prognostic information, especially in PMF [7,[20][21][22]. Interestingly, it has been reported that the sequential induction of DNMT3A and nucleophosmin (NPM1) mutations in genetically engineered mice can generate an MPN-like disorder, following a condition of clonal hematopoiesis [23].…”

Section: Introductionmentioning

confidence: 99%

Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies

Nasillo

Riva

Paolini

et al. 2021

IJMS

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The Philadelphia-negative myeloproliferative neoplasms (MPNs) are malignancies of the hematopoietic stem cell (HSC) arising as a consequence of clonal proliferation driven by somatically acquired driver mutations in discrete genes (JAK2, CALR, MPL). In recent years, along with the advances in molecular characterization, the role of immune dysregulation has been achieving increasing relevance in the pathogenesis and evolution of MPNs. In particular, a growing number of studies have shown that MPNs are often associated with detrimental cytokine milieu, expansion of the monocyte/macrophage compartment and myeloid-derived suppressor cells, as well as altered functions of T cells, dendritic cells and NK cells. Moreover, akin to solid tumors and other hematological malignancies, MPNs are able to evade T cell immune surveillance by engaging the PD-1/PD-L1 axis, whose pharmacological blockade with checkpoint inhibitors can successfully restore effective antitumor responses. A further interesting cue is provided by the recent discovery of the high immunogenic potential of JAK2V617F and CALR exon 9 mutations, that could be harnessed as intriguing targets for innovative adoptive immunotherapies. This review focuses on the recent insights in the immunological dysfunctions contributing to the pathogenesis of MPNs and outlines the potential impact of related immunotherapeutic approaches.

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Co-existence of mutations in myeloproliferative neoplasms and their clinical significance: a prognostic approach

Cited by 3 publications

References 62 publications

Molecular Progression of Myeloproliferative and Myelodysplastic/Myeloproliferative Neoplasms: A Study on Sequential Bone Marrow Biopsies

Molecular Progression of Myeloproliferative and Myelodysplastic/Myeloproliferative Neoplasms: A Study on Sequential Bone Marrow Biopsies

Progression in Myeloid Neoplasms: Beyond the Myeloblast

Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies

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