Impact of NFE2 mutations on AML transformation and overall survival in patients with myeloproliferative neoplasms

Marcault, Clémence; Zhao, Lin; Maslah, Nabih; Verger, E.; Oliveira, Rafael Daltro De; Soret-Dulphy, Juliette; Cazaux, Marine; Gauthier, Nicolas; Roux, Bénédicte Gaillard-Le; Clappier, Emmanuelle; Parquet, Nathalie; Dosquet, Christine; Réa, Delphine; Zini, Jean‐Marc; Vainchenker, William; Raffoux, Emmanuel; Giraudier, Stéphane; Kiladjian, Jean‐Jacques; Cassinat, Bruno; Benajiba, Lina

doi:10.1182/blood.2020010402

Cited by 25 publications

(13 citation statements)

References 10 publications

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“…Conversely, in a larger recent study, multivariate analysis of the data from 707 patients with MPNs (113 PMF, 233 PV, 332 ET) and available NGS data demonstrated that NF-E2 mutations (VAF ≥ 5%) carried a hazard ratio (HR) of 10.29 for transformation to AML (independently from age and co-occurring HMR mutations) and an HR of 8.24 for OS [ 117 ]. The HR of NF-E2 mutations was about fivefold higher for leukemogenesis and fourfold higher for OS compared to HMR mutations, respectively, thereby associating NF-E2 gene mutations with an aggressive disease course [ 117 ]. Notably, the NF-E2 VAF decreased at the time of leukemic transformation compared to the chronic phase, indicating that NF-E2 -mutated cells may be outcompeted by another new dominant clone.…”

Section: Introductionmentioning

confidence: 99%

“…Patients harboring NF-E2 mutations had a higher median hematocrit than non-mutated patients in line with its association with the myeloproliferative phenotype and higher incidence in PV (7.3%) vs. PMF (5.3%) and ET (3.6%) [ 117 ]. As previously noted, NF-E2 mutations were acquired later in the disease course [ 25 ], induced significantly lower rates of hematological responses leading to the necessity for more lines of treatment, and were detected in 40% of the patients who lost response to treatment [ 117 ]. On the basis of these findings, analysis of NF-E2 mutations can be performed at diagnosis and in follow-up or upon loss of response to treatment.…”

Section: Introductionmentioning

confidence: 99%

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Biological drivers of clinical phenotype in myelofibrosis

et al. 2022

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Myelofibrosis (MF) is a myeloproliferative disorder that exhibits considerable biological and clinical heterogeneity. At the two ends of the disease spectrum are the myelodepletive or cytopenic phenotype and the myeloproliferative phenotype. The cytopenic phenotype has a high prevalence in primary MF (PMF) and is characterized by low blood counts. The myeloproliferative phenotype is typically associated with secondary MF (SMF), mild anemia, minimal need for transfusion support, and normal to mild thrombocytopenia. Differences in somatic driver mutations and allelic burden, as well as the acquisition of non-driver mutations further influences these phenotypic differences, prognosis, and response to therapies such as JAK2 inhibitors. The outcome of patients with the cytopenic phenotype are comparatively worse and frequently pose a challenge to treat given the inherent exacerbation of cytopenias. Recent data indicate that an innate immune deregulated state that hinges on the myddosome-IRAK-NFκB axis favors the cytopenic myelofibrosis phenotype and offers opportunity for novel treatment approaches. We will review the biological and clinical features of the MF disease spectrum and associated treatment considerations.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Biological drivers of clinical phenotype in myelofibrosis

et al. 2022

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“…Notably, NFE2 was mutated in 3 unrelated patients, including two nonsense mutations and one missense mutation in the important BRLZ domain (Figure 4A). NFE2 encodes a transcription factor involved in megakaryocyte development and platelet production 25,26 , which is mutated in more than 1% of MDS and around 0.7% of leukemia patients 27,28 (Figure 4B). However, NFE2 has not been reported as a gene associated with clonal hematopoiesis.…”

Section: Resultsmentioning

confidence: 99%

Genomic Landscape of Patients with GermlineRUNX1Variants and Familial Platelet Disorder with Myeloid Malignancy

Yu¹,

Deuitch²,

Merguerian

et al. 2023

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Germline RUNX1 mutations lead to familial platelet disorder with associated myeloid malignancies (FPDMM), which is characterized by thrombocytopenia and a life-long risk (35-45%) of hematological malignancies. We recently launched a longitudinal natural history study for patients with FPDMM at the NIH Clinical Center. Among 29 families with research genomic data, 28 different germline RUNX1 variants were detected. Besides missense mutations enriched in Runt homology domain and loss-of-function mutations distributed throughout the gene, splice-region mutations and large deletions were detected in 6 and 7 families, respectively. In 24 of 54 (44.4%) non-malignant patients, somatic mutations were detected in at least one of the clonal hematopoiesis of indeterminate potential (CHIP) genes or acute myeloid leukemia (AML) driver genes. BCOR was the most frequently mutated gene (in 9 patients), and multiple BCOR mutations were identified in 4 patients. Mutations in 7 other CHIP or AML driver genes (DNMT3A, TET2, NRAS, SETBP1, SF3B1, KMT2C, and LRP1B) were also found in more than one non-malignant patient. Moreover, three unrelated patients (one with myeloid malignancy) carried somatic mutations in NFE2, which regulates erythroid and megakaryocytic differentiation. Sequential sequencing data from 19 patients demonstrated dynamic changes of somatic mutations over time, and stable clones were more frequently found in elderly patients. In summary, there are diverse types of germline RUNX1 mutations and high frequency of somatic mutations related to clonal hematopoiesis in patients with FPDMM. Monitoring dynamic changes of somatic mutations prospectively will benefit patients' clinical management and reveal mechanisms for progression to myeloid malignancies.

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“…In a retrospective analysis of post-MPN AML patients, using the Mantel-Byar test to control for immortality bias, allo-SCT failed to significantly improve OS [ 58 ]. There is also discussion about the timing of transplant and whether or not it should be considered in high-risk patients prior to LT. Interestingly, Marcault et al found that somatic mutations of nuclear factor erythroid 2 (NFE2 ) were detected at different time points during the MPN disease course and were associated with loss of treatment response [ 59 ]. Taken together, further work to identify signals to prompt transplant, such as NFE2 mutations, before MPN patients transform to leukemia may be a promising area of future research.…”

Section: Standard Treatment Options: Medically Fit Patientsmentioning

confidence: 99%

Acute Myeloid Leukemia Following Myeloproliferative Neoplasms: A Review of What We Know, What We Do Not Know, and Emerging Treatment Strategies

et al. 2022

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Acute myeloid leukemia (AML) arising from myeloproliferative neoplasms (MPNs) represents a small subtype of secondary AML (sAML). This entity is well known to be associated with poor responses to available treatment options and dismal outcomes. To date, there are no standardized treatment options and there has been very little therapeutic advancement in recent years. This is a stark contrast to other subsets of AML for which there have been significant advances in therapeutic approaches, especially for patients with targetable mutations. We aim to focus our review on the incidence, risk factors for leukemogenesis, pathogenesis, molecular landscape, and emerging therapeutic options in post-myeloproliferative neoplasm acute myeloid leukemia (post-MPN AML).

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Impact of NFE2 mutations on AML transformation and overall survival in patients with myeloproliferative neoplasms

Cited by 25 publications

References 10 publications

Biological drivers of clinical phenotype in myelofibrosis

Biological drivers of clinical phenotype in myelofibrosis

Genomic Landscape of Patients with GermlineRUNX1Variants and Familial Platelet Disorder with Myeloid Malignancy

Acute Myeloid Leukemia Following Myeloproliferative Neoplasms: A Review of What We Know, What We Do Not Know, and Emerging Treatment Strategies

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