Noonan syndrome‐associated myeloproliferative disorder with somatically acquired monosomy 7: impact on clinical decision making

Hofmans, Mattias; Schröder, Rieke; Lammens, Tim; Flotho, Christian; Niemeyer, Charlotte M.; Roy, Nadine Van; Decaluwe, Wim; Philippé, Jan; Moerloose, Barbara De

doi:10.1111/bjh.16191

Cited by 14 publications

(7 citation statements)

References 11 publications

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“…‡Germline mutation, patients generally display syndromic features of Noonan syndrome. §In rare instances, monosomy 7 can develop 261,262. 1214 blood® 15 SEPTEMBER 2022 | VOLUME 140, NUMBER 11 young patients.…”

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confidence: 99%

International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data

Arber

Orazi

Hasserjian

et al. 2022

Blood

1,379

778

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The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CAC) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.

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confidence: 99%

International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data

Arber

Orazi

Hasserjian

et al. 2022

Blood

1,379

778

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“…Although the condition is indistinguishable from JMML by clinical and hematological features, it has a self-limiting course in the vast majority of cases. Only a small fraction of children with NS/MPD progress to JMML, presumably after the acquisition of additional genetic changes [ 5 , 47 ]. Although the landscape of PTPN11 mutations is not identical in JMML and NS/MPD [ 31 ], there is considerable overlap, and it is not well understood how the same mutation elicits a transient disorder when present in the germline and a fatal disorder when acquired somatically.…”

Section: The Origin Of Jmml: the Ras Pathwaymentioning

confidence: 99%

“…However, these patients must be monitored carefully, as there can be relevant clinical compromise from cell infiltrates, making it necessary to begin cytoreductive therapy. In individual cases, a clonal development towards a bona fide neoplastic disease is possible [ 47 , 102 , 103 ].…”

Section: Current Recommendations For the Management Of Jmmlmentioning

confidence: 99%

Current Treatment of Juvenile Myelomonocytic Leukemia

Mayerhofer

Niemeyer

Flotho

2021

JCM

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Juvenile myelomonocytic leukemia (JMML) is a rare pediatric leukemia characterized by mutations in five canonical RAS pathway genes. The diagnosis is made by typical clinical and hematological findings associated with a compatible mutation. Although this is sufficient for clinical decision-making in most JMML cases, more in-depth analysis can include DNA methylation class and panel sequencing analysis for secondary mutations. NRAS-initiated JMML is heterogeneous and adequate management ranges from watchful waiting to allogeneic hematopoietic stem cell transplantation (HSCT). Upfront azacitidine in KRAS patients can achieve long-term remissions without HSCT; if HSCT is required, a less toxic preparative regimen is recommended. Germline CBL patients often experience spontaneous resolution of the leukemia or exhibit stable mixed chimerism after HSCT. JMML driven by PTPN11 or NF1 is often rapidly progressive, requires swift HSCT and may benefit from pretransplant therapy with azacitidine. Because graft-versus-leukemia alloimmunity is central to cure high risk patients, the immunosuppressive regimen should be discontinued early after HSCT.

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“…More recently, investigations of secondary mutations 5,6 , non-coding RNA expression 7,8 , and genomic DNA methylation 9-11 have led to a better understanding of the pathobiology of the disease. The acquisition of secondary mutations and aberrant DNA methylation were found to be associated with unfavorable clinical characteristics and poor prognosis, and might be used in the future to guide treatment decisions 5,12 . Furthermore,…”

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Long non-coding RNAs as novel therapeutic targets in juvenile myelomonocytic leukemia

Hofmans

Lammens

Depreter³

et al. 2021

Sci Rep

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Juvenile myelomonocytic leukemia (JMML) treatment primarily relies on hematopoietic stem cell transplantation and results in long-term overall survival of 50–60%, demonstrating a need to develop novel treatments. Dysregulation of the non-coding RNA transcriptome has been demonstrated before in this rare and unique disorder of early childhood. In this study, we investigated the therapeutic potential of targeting overexpressed long non-coding RNAs (lncRNAs) in JMML. Total RNA sequencing of bone marrow and peripheral blood mononuclear cell preparations from 19 untreated JMML patients and three healthy children revealed 185 differentially expressed lncRNA genes (131 up- and 54 downregulated). LNA GapmeRs were designed for 10 overexpressed and validated lncRNAs. Molecular knockdown (≥ 70% compared to mock control) after 24 h of incubation was observed with two or more independent GapmeRs in 6 of them. For three lncRNAs (lnc-THADA-4, lnc-ACOT9-1 and NRIR) knockdown resulted in a significant decrease of cell viability after 72 h of incubation in primary cultures of JMML mononuclear cells, respectively. Importantly, the extent of cellular damage correlated with the expression level of the lncRNA of interest. In conclusion, we demonstrated in primary JMML cell cultures that knockdown of overexpressed lncRNAs such as lnc-THADA-4, lnc-ACOT9-1 and NRIR may be a feasible therapeutic strategy.

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Noonan syndrome‐associated myeloproliferative disorder with somatically acquired monosomy 7: impact on clinical decision making

Cited by 14 publications

References 11 publications

International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data

International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data

Current Treatment of Juvenile Myelomonocytic Leukemia

Long non-coding RNAs as novel therapeutic targets in juvenile myelomonocytic leukemia

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