RUNX1T1 – Acute Myeloid Leukemia with t(8;21)

RUNX1T1 (also known as MTG8 or ETO) encodes a transcriptional corepressor that, when fused to RUNX1 via the t(8;21)(q22;q22) translocation, produces the RUNX1-RUNX1T1 oncoprotein central to acute myeloid leukemia (AML) pathogenesis. This fusion is a defining molecular marker in 5–10% of de novo AML, predominantly the French-American-British M2 subtype, and underlies a distinct clinical and biological entity. Cytogenetic and molecular assays such as FISH and RT-PCR routinely detect this fusion, supporting its diagnostic utility and prognostic stratification.

Multiple large cohorts corroborate the recurrence of RUNX1-RUNX1T1 in AML M2. In a collaborative cytogenetic study of 638 pediatric AML patients, 74 (11.6%) harbored the classic t(8;21) and seven (1.1%) exhibited complex variants involving 8q22 and 21q22, all with M2 morphology and Auer rods (PMID:8055478). Additional analyses in 652 AML M0–M2 cases confirmed t(8;21) in 12.5% of M2 and rare occurrences in M1 (1.7%), consolidating the fusion’s specificity for this subtype (PMID:15527902).

Beyond canonical translocations, variant rearrangements incorporating chromosomes 4, 6, 12, 13, 18, and 19 also yield in-frame RUNX1-RUNX1T1 fusions with similar molecular features, although co-occurring cytogenetic abnormalities (e.g., trisomy 6) can modulate prognosis (PMID:19167612). Across studies, over 600 unrelated AML M2 probands harboring RUNX1-RUNX1T1 fusions have been documented, establishing a robust genotype–phenotype correlation.

Functional investigations demonstrate that RUNX1-RUNX1T1 acts as a dominant transcriptional repressor of RUNX1 target genes, recruits corepressors, and alters transcriptional programs in myeloid progenitors. The fusion protein directly represses tumor suppressors such as NF1, enhances cytokine sensitivity, and requires cooperating lesions to induce leukemia in mouse models (PMID:15988004, PMID:23426948). Alternative splicing and dimerization changes further potentiate its leukemogenicity.

No conflicting evidence disputes the RUNX1-RUNX1T1 fusion as a causative driver in core binding factor AML. The consistency of cytogenetic detection, molecular confirmation, and functional modeling over three decades underscores a definitive gene–disease relationship.

Key Take-home: The somatic RUNX1-RUNX1T1 fusion is a definitive, recurrent lesion in AML M2, essential for diagnosis, risk stratification, and guiding targeted research into core binding factor leukemias.

References

• Cancer genetics and cytogenetics • 1994 • Variant t(8;21) rearrangements in acute myeloblastic leukemia of childhood. PMID:8055478
• Cancer genetics and cytogenetics • 2004 • Cytogenetic profile in de novo acute myeloid leukemia with FAB subtypes M0, M1, and M2: a study based on 652 cases analyzed with morphology, cytogenetics, and fluorescence in situ hybridization. PMID:15527902
• Molecular and cellular biology • 2005 • Transcriptional repression of the Neurofibromatosis-1 tumor suppressor by the t(8;21) fusion protein. PMID:15988004
• Blood • 2013 • Attenuation of AML1-ETO cellular dysregulation correlates with increased leukemogenic potential. PMID:23426948

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