Non-driver mutations landscape in different stages of primary myelofibrosis determined ASXL1 mutations play a critical role in disease progression

Yan, Xin; Xu, Zefeng; Zhang, Peihong; Sun, Qi; Jia, Yujiao; Qin, Tiejun; Qu, Shiqiang; Pan, Lijuan; Li, Zhanqi; Liu, Jinqin; Song, Zhen; Gao, Qingyan; Jiao, Meng; Gong, Jingye; Wang, Huijun; Li, Bing; Xiao, Zhijian

doi:10.1038/s41408-023-00829-3

Cited by 2 publications

(4 citation statements)

References 16 publications

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“…At diagnosis, the prevalence of TP53 mutations may not be high enough to be statistically significant. RUNX1 mutation has been linked to inferior survival or transformation to acute leukemia in a few studies [29,39,42]. In a study of 363 patients with PMF, mutations in CBL, NRAS, KRAS, RUNX1, and TP53 did not show significant prognostic value [110].…”

Section: Implications In the Prognosismentioning

confidence: 99%

“…ASXL1 mutation has the highest prevalence, close to 50% in PMF and 30-40% in SMF in some studies [40,41]. Yan et al studied 258 consecutive PMF patients with 275 samples by sequencing 27 genes, with 17 patients tested on at least two time points, and found that the variant allele frequency (VAF) of ASXL1 mutations was relatively stable during the disease process [42]. Luque et al reported that ZRSR2 and NFE2 mutations were more common in SMF [41].…”

Section: Additional Mutationsmentioning

confidence: 99%

“…Additionally, various studies have revealed prognostic associations with other mutations. ASXL1 is the second most frequently mutated gene in MF after JAK2 V617F and has demonstrated significant associations with progression from prefibrotic to overt PMF, transformation to accelerated and blast phases, and an overall worse prognosis [42,113]. Notably, mutations in ASXL1 are frequently observed in CHIP, which increases with age.…”

Section: Implications In the Prognosismentioning

confidence: 99%

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Molecular Genetic Profile of Myelofibrosis: Implications in the Diagnosis, Prognosis, and Treatment Advancements

Verma,

Papadantonakis,

Peker Barclift

et al. 2024

Cancers

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Myelofibrosis (MF) is an essential element of primary myelofibrosis, whereas secondary MF may develop in the advanced stages of other myeloid neoplasms, especially polycythemia vera and essential thrombocythemia. Over the last two decades, advances in molecular diagnostic techniques, particularly the integration of next-generation sequencing in clinical laboratories, have revolutionized the diagnosis, classification, and clinical decision making of myelofibrosis. Driver mutations involving JAK2, CALR, and MPL induce hyperactivity in the JAK-STAT signaling pathway, which plays a central role in cell survival and proliferation. Approximately 80% of myelofibrosis cases harbor additional mutations, frequently in the genes responsible for epigenetic regulation and RNA splicing. Detecting these mutations is crucial for diagnosing myeloproliferative neoplasms (MPNs), especially in cases where no mutations are present in the three driver genes (triple-negative MPNs). While fibrosis in the bone marrow results from the disturbance of inflammatory cytokines, it is fundamentally associated with mutation-driven hematopoiesis. The mutation profile and order of acquiring diverse mutations influence the MPN phenotype. Mutation profiling reveals clonal diversity in MF, offering insights into the clonal evolution of neoplastic progression. Prognostic prediction plays a pivotal role in guiding the treatment of myelofibrosis. Mutation profiles and cytogenetic abnormalities have been integrated into advanced prognostic scoring systems and personalized risk stratification for MF. Presently, JAK inhibitors are part of the standard of care for MF, with newer generations developed for enhanced efficacy and reduced adverse effects. However, only a minority of patients have achieved a significant molecular-level response. Clinical trials exploring innovative approaches, such as combining hypomethylation agents that target epigenetic regulators, drugs proven effective in myelodysplastic syndrome, or immune and inflammatory modulators with JAK inhibitors, have demonstrated promising results. These combinations may be more effective in patients with high-risk mutations and complex mutation profiles. Expanding mutation profiling studies with more sensitive and specific molecular methods, as well as sequencing a broader spectrum of genes in clinical patients, may reveal molecular mechanisms in cases currently lacking detectable driver mutations, provide a better understanding of the association between genetic alterations and clinical phenotypes, and offer valuable information to advance personalized treatment protocols to improve long-term survival and eradicate mutant clones with the hope of curing MF.

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Section: Implications In the Prognosismentioning

confidence: 99%

Section: Additional Mutationsmentioning

confidence: 99%

Section: Implications In the Prognosismentioning

confidence: 99%

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Molecular Genetic Profile of Myelofibrosis: Implications in the Diagnosis, Prognosis, and Treatment Advancements

Verma,

Papadantonakis,

Peker Barclift

et al. 2024

Cancers

View full text Add to dashboard Cite

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“…Accordingly, mutant- ASXL1 patients with MF and an Asxl1 −/− Jak2 VF ( Asxl1 deletion/ Jak2 V617F) mouse model demonstrated accelerated bone marrow fibrosis compared to the wild-type ASXL1 cohort and the Jak2 VF littermate, respectively [ 66 ]. Furthermore, a significant association was found between ASXL1 mutations and fibrosis as well as disease progression in another recent study of 258 patients with PMF [ 67 ]. Notably, extremely high hazard ratios were reported for mutations in the nuclear factor erythroid-2 ( NFE2 ) gene, a hematopoietic transcription factor, for leukemic transformation or progression to MDS and OS (10.3 and 8.24, respectively; p < 0.001); and the rates of hematological response to treatment were significantly lower ( p = 0.026) [ 68 ].…”

Section: Genes Associated With the Myeloproliferative And Myelodeplet...mentioning

confidence: 99%

Association of Myelofibrosis Phenotypes with Clinical Manifestations, Molecular Profiles, and Treatments

Chifotides

Verstovšek

Bose

2023

Cancers

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Myelofibrosis (MF) presents an array of clinical manifestations and molecular profiles. The two distinct phenotypes− myeloproliferative and myelodepletive or cytopenic− are situated at the two poles of the disease spectrum and are largely defined by different degrees of cytopenias, splenomegaly, and distinct molecular profiles. The myeloproliferative phenotype is characterized by normal/higher peripheral blood counts or mildly decreased hemoglobin, progressive splenomegaly, and constitutional symptoms. The myeloproliferative phenotype is typically associated with secondary MF, higher JAK2 V617F burden, fewer mutations, and superior overall survival (OS). The myelodepletive phenotype is usually associated with primary MF, ≥2 cytopenias, modest splenomegaly, lower JAK2 V617F burden, higher fibrosis, greater genomic complexity, and inferior OS. Cytopenias are associated with mutations in epigenetic regulators/splicing factors, clonal evolution, disease progression, and shorter OS. Clinical variables, in conjunction with the molecular profiles, inform integrated prognostication and disease management. Ruxolitinib/fedratinib and pacritinib/momelotinib may be more suitable to treat patients with the myeloproliferative and myelodepletive phenotypes, respectively. Appreciation of MF heterogeneity and two distinct phenotypes, the different clinical manifestations and molecular profiles associated with each phenotype alongside the growing treatment expertise, the development of non-myelosuppressive JAK inhibitors, and integrated prognostication are leading to a new era in patient management. Physicians can increasingly tailor personalized treatments that will address the unique unmet needs of MF patients, including those presenting with the myelodepletive phenotype, to elicit optimal outcomes and extended OS across the disease spectrum.

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Non-driver mutations landscape in different stages of primary myelofibrosis determined ASXL1 mutations play a critical role in disease progression

Cited by 2 publications

References 16 publications

Molecular Genetic Profile of Myelofibrosis: Implications in the Diagnosis, Prognosis, and Treatment Advancements

Molecular Genetic Profile of Myelofibrosis: Implications in the Diagnosis, Prognosis, and Treatment Advancements

Association of Myelofibrosis Phenotypes with Clinical Manifestations, Molecular Profiles, and Treatments

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