ANKRD26 – ANKRD26-related Acute Myeloid Leukemia Predisposition

Autosomal-dominant germline variants in ANKRD26 predispose to inherited thrombocytopenia 2 (THC2) and carry a documented risk for progression to acute myeloid leukemia (AML). ANKRD26 was first recognized as an AML predisposition locus in familial THC2 cohorts and broader myeloid malignancy reviews (PMID:27248996).

In a study of 250 apparently sporadic adult AML patients, four individuals (1.6%) harbored germline ANKRD26 variants: one c.-125T>G 5'UTR substitution and three N-terminal truncating mutations (c.3G>A and c.105C>G) resulting in stable truncated proteins (PMID:28100250). The patient with c.-125T>G had unrecognized familial THC2, confirming autosomal-dominant segregation.

Variant spectrum in AML includes monoallelic 5'UTR substitutions (n=1) and coding region truncations (n=3). No splice or deep-intronic variants were reported in this cohort, and no recurrent founder alleles specific to AML have been described.

Functional assays demonstrate that both UTR and truncating mutations abolish RUNX1/FLI1 binding, derepress ANKRD26 expression, and hyperactivate MAPK/ERK signaling in megakaryocytic cells, impairing proplatelet formation; ERK inhibition rescues this defect (PMID:24430186). In vivo, N-terminal truncations drive ANKRD26 overexpression, corroborating the mechanistic basis for AML predisposition (PMID:28100250).

No large pedigrees with segregating AML-only phenotypes have been described, and the contribution of novel variants of uncertain significance remains under investigation. A recent case report identified a VUS (c.4227dup), underscoring the need for functional classification in AML contexts (PMID:37065357).

Integration of genetic and experimental data supports a Moderate ClinGen gene–disease association: multiple unrelated probands with pathogenic ANKRD26 variants and concordant functional studies. Genetic evidence is Moderate (four AML probands with germline UTR and truncating variants, one with familial segregation), and functional evidence is Moderate (consistent in vitro mechanistic and rescue data).

Key Take-home: Germline ANKRD26 testing should be considered in AML patients, particularly those with personal or family history of thrombocytopenia, to guide donor selection and surveillance strategies.

References

• International journal of molecular sciences • 2016 • Hereditary Predispositions to Myelodysplastic Syndrome. PMID:27248996
• Journal of hematology & oncology • 2017 • 5'UTR point substitutions and N-terminal truncating mutations of ANKRD26 in acute myeloid leukemia. PMID:28100250
• The Journal of clinical investigation • 2014 • Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation. PMID:24430186
• Cureus • 2023 • ANKRD26 Gene Variant of Uncertain Significance in a Patient With Acute Myeloid Leukemia. PMID:37065357

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