3  ANKRD26

• Ankyrin repeat domain 26 (ANKRD26)
• ANKRD26 is a highly conserved gene located on chromosome 10p12.1 which has shown to play a role in normal megakaryocyte differentiation.
• These mutations result in mild-moderate thrombocytopenia and a 20-30-fold increased risk of myeloid malignancy
• Mechanism: Single nucleotide variants affecting the 5’untranslated region or N-terminus (5’UTR) of ANKRD26 result in its de-repression, impacting megakaryopoiesis by modulating type I cytokine signaling through induction of MAPK hyperactivation. Bluteau et al. (2014); Basso-Valentina et al. (2023)

3.1 ANKRD26-RT

3.1.1 Eight patients with ANKRD26-RT from five families. Wahlster et al. (2025)

3.1.2 Risk of Hematologic Neoplasms

• AML and MDS are the most commonly described, though there are some reports of lymphoid malignancies
• a single case report of a patient with a 5’UTR mutation developing multiple myeloma.
• An extended case series of 118 subjects with confirmed or highly probable ANKRD26-RT revealed an 8% incidence of myeloid malignancy (AML, MDS, and chronic myeloid leukemia (CML)). Noris et al. (2011)
• An estimated 24-fold increase in acute leukemia incidence alone is reported compared to the general population in this study

3.1.3 Risk of Thrombosis

3.2 WAC::ANKRD26 fusion

• Familial thrombocytopenia secondary to germline WAC::ANKRD26 fusion shares key clinical and biological features with classical thrombocytopenia 2(THC2), including thrombocytopenia and hyperactive ERK signaling, but represents a genetically distinct alteration characterized by aberrant overexpression of N-terminally truncated ANKRD26 (exons 11-34) under the WAC promoter. Wahlster et al. (2021)

Basso-Valentina, Francesca, Alessandro Donada, Vladimir T Manchev, et al. 2023. “ANKRD26 Is a New Regulator of Type i Cytokine Receptor Signaling in Normal and Pathological Hematopoiesis.” Haematologica 108 (8): 2130–45. https://doi.org/10.3324/haematol.2022.282049.

Bluteau, Dominique, Alessandra Balduini, Nathalie Balayn, et al. 2014. “Thrombocytopenia-Associated Mutations in the ANKRD26 Regulatory Region Induce MAPK Hyperactivation.” Journal of Clinical Investigation 124 (2): 580–91. https://doi.org/10.1172/jci71861.

Noris, Patrizia, Silverio Perrotta, Marco Seri, et al. 2011. “Mutations in ANKRD26 Are Responsible for a Frequent Form of Inherited Thrombocytopenia: Analysis of 78 Patients from 21 Families.” Blood 117 (24): 6673–80. https://doi.org/10.1182/blood-2011-02-336537.

Wahlster, Lara, Lucy A Godley, Jason X Cheng, et al. 2025. “ANKRD26-Related Thrombocytopenia 2 with a Baseline Increase in Blasts: Implications for Clinical Surveillance.” Blood Journal, ahead of print, May 7. https://doi.org/10.1182/blood.2024027368.

Wahlster, Lara, Jeffrey M. Verboon, Leif S. Ludwig, et al. 2021. “Familial Thrombocytopenia Due to a Complex Structural Variant Resulting in a WAC-ANKRD26 Fusion Transcript.” Journal of Experimental Medicine 218 (6). https://doi.org/10.1084/jem.20210444.