ERG – Acute Myeloid Leukemia

ETS-related gene ERG is implicated in the pathogenesis of acute myeloid leukemia (Disease Name) through recurrent somatic gene fusions and transcript overexpression. In a 2-year-old girl with AML, RNA-sequencing revealed a cryptic FUS-ERG fusion joining FUS exon 7 to ERG exon 8, encoding a 497-amino-acid chimeric oncoprotein; similar fusions were reported in two other infant leukemias (PMID:24068373). High ERG transcript levels have been associated with inferior event-free survival in pediatric cohorts and poor outcomes in adult AML (PMID:21967978).

Genetic evidence centers on somatic FUS-ERG fusions that retain the FUS transactivation domains TR1/TR2 and the ERG ETS DNA-binding domain, driving leukemic transformation in at least three unrelated pediatric probands (PMID:24068373). No recurrent point mutations in ERG have been documented in AML, but ERG amplifications and aberrant splicing isoforms have been observed in high-risk subgroups.

Expression profiling in 149 pediatric AML patients demonstrated that elevated ERG mRNA predicts inferior event-free survival, independent of FLT3-ITD and NPM1 status (PMID:21967978). Likewise, adult AML cohorts show that ERG overexpression stratifies patients into high-risk categories, underscoring its prognostic value.

Functional assays corroborate an oncogenic role: overexpression of ERG in murine fetal liver progenitors cooperates with GATA1s mutations to immortalize megakaryocytic precursors, while ERG knockdown impairs proliferation in leukemia cell lines (PMID:18692240). MicroRNA regulation studies identify miR-196a/b as direct ERG repressors, affecting hematopoietic differentiation (PMID:20570349).

In GATA2 haploinsufficient mouse models, human ERG expression accelerates AML onset and reveals a conserved mitochondrial signature also seen in patients with germline GATA2 mutations (PMID:36475518). No studies have refuted ERG’s contribution to AML leukemogenesis.

Collectively, somatic ERG fusions and overexpression provide moderate genetic and functional evidence supporting ERG as an oncogenic driver in AML. ERG status offers prognostic stratification and emerges as a candidate for targeted therapy. Key Take-Home: Assessing ERG rearrangements and transcript levels can improve AML risk classification and inform therapeutic development.

References

• Oncology reports • 2013 • Cryptic FUS-ERG fusion identified by RNA-sequencing in childhood acute myeloid leukemia. PMID:24068373
• Blood • 2011 • Presence of FLT3-ITD and high BAALC expression are independent prognostic markers in childhood acute myeloid leukemia. PMID:21967978
• Leukemia research • 2009 • Physical and functional interactions between hematopoietic cell-specific ETS transcription factors and homeodomain proteins. PMID:18692240
• Leukemia research • 2011 • The role of microRNA-196a and microRNA-196b as ERG regulators in acute myeloid leukemia and acute T-lymphoblastic leukemia. PMID:20570349
• Haematologica • 2023 • Cellular and metabolic characteristics of pre-leukemic hematopoietic progenitors with GATA2 haploinsufficiency. PMID:36475518

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