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The transcription factor NFE2 (HGNC:7780) has been recurrently identified in adult acute myeloid leukemia (MONDO_0018874) cases. In a large multi‐patient study of 292 individuals with core binding factor leukemia, recurrent NFE2 mutations were observed in approximately 3% of cases (PMID:31896782), suggesting that, although infrequent, NFE2 alterations contribute to leukemogenesis.
Assessing the clinical validity, the overall evidence supports a Moderate ClinGen classification. The study identified roughly 9 unrelated probands with NFE2 mutations in a well‐characterized cohort, and while detailed segregation data are not applicable for acquired somatic events, the repeated detection of these alterations is compelling (PMID:31896782).
Genetic evidence is bolstered by the recurrent nature of the mutations observed in independent AML cohorts. Although no specific HGVS variant was provided in the available data, the aggregation of these findings across multiple cases contributes to a moderate level of genetic evidence for NFE2 involvement. There is no applicable family segregation given the somatic nature of this mutation.
Functional studies further support a role for NF-E2 in hematopoietic regulation. Experiments in mouse erythroleukemia cells have demonstrated that disruption of NF-E2 activity impairs globin gene expression (PMID:7623856), and additional research has shown that NF-E2 is critical for proper megakaryocyte biogenesis and hematopoietic differentiation (PMID:14565864). These results provide mechanistic insight into how NFE2 alterations may facilitate leukemic transformation.
Despite the supportive genetic and functional evidence, some uncertainty remains regarding the magnitude of NFE2’s impact on clinical outcomes. Conflicting results in broader studies of myeloid malignancies suggest that additional genetic or epigenetic modifiers might influence disease progression. Nevertheless, the combined data offer a coherent narrative linking NFE2 dysfunction to AML pathogenesis.
In summary, the integration of moderate genetic data from AML patient cohorts and corroborative experimental findings assigns a Moderate ClinGen score to the association between NFE2 and acute myeloid leukemia. This evidence is robust enough to inform diagnostic decision‑making and guide future targeted therapeutic strategies.
Key Take‑home sentence: Recurrent NFE2 alterations, although present in a minority of AML cases, are supported by functional mechanisms and constitute a moderate level of evidence with significant clinical utility.
Gene–Disease AssociationModerateApproximately 9 unrelated AML probands in a cohort of 292 patients exhibited recurrent NFE2 mutations (PMID:31896782); the evidence is reinforced by consistent experimental data. Genetic EvidenceModerateRecurrent NFE2 alterations have been identified in independent AML cohorts, despite the absence of a detailed variant description, supporting its contributory role in leukemogenesis. Functional EvidenceModerateMultiple functional studies demonstrate that NF-E2 is essential for hematopoietic gene regulation and differentiation, which bolsters its proposed involvement in AML pathogenesis (PMID:7623856, PMID:14565864). |