5’UTR point substitutions and N-terminal truncating mutations of ANKRD26 in acute myeloid leukemia

Abstract

Thrombocytopenia 2 (THC2) is an inherited disorder caused by monoallelic single nucleotide substitutions in the 5’UTR of the ANKRD26 gene. Patients have thrombocytopenia and increased risk of myeloid malignancies, in particular, acute myeloid leukemia (AML). Given the association of variants in the ANKRD26 5’UTR with myeloid neoplasms, we investigated whether, and to what extent, mutations in this region contribute to apparently sporadic AML. To this end, we studied 250 consecutive, non-familial, adult AML patients and screened the first exon of ANKRD26 including the 5’UTR. We found variants in four patients. One patient had the c.−125T>G substitution in the 5’UTR, while three patients carried two different variants in the 5’ end of the ANKRD26 coding region (c.3G>A or c.105C>G). Review of medical history showed that the patient carrying the c.−125T>G was actually affected by typical but unrecognized THC2, highlighting that some apparently sporadic AML cases represent the evolution of a well-characterized familial predisposition disorder. As regards the c.3G>A and the c.105C>G, we found that both variants result in the synthesis of N-terminal truncated ANKRD26 isoforms, which are stable and functional in cells, in particular, have a strong ability to activate the MAPK/ERK signaling pathway. Moreover, investigation of one patient with the c.3G>A showed that mutation was associated with strong ANKRD26 overexpression in vivo, which is the proposed mechanism for predisposition to AML in THC2 patients. These data provide evidence that N-terminal ANKRD26 truncating mutations play a potential pathogenetic role in AML. Recognition of AML patients with germline ANKRD26 pathogenetic variants is mandatory for selection of donors for bone marrow transplantation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0382-y) contains supplementary material, which is available to authorized users.

Thrombopoietin receptor agonists in hereditary thrombocytopenias

“…Proplatelet formation and platelet release Clinical trial ongoing [42] ANKRD26-related thrombocytopenia (ANKRD26-RT, 188000) [40,44] ANKRD26…”

Myeloid Neoplasm With Germline Predisposition: A 2016 Update for Pathologists

“…41,42 Accumulating evidence indicates that the 5 0 untranslated region mutations cause ANKRD26 overexpression because of defective inhibitory regulation of RUNX1 and FLI1, and this leads to disruption of the thrombopoietin/myeloproliferative leukemia virus oncogene pathway, which is important for platelet formation by megakaryocytes. 41,43 Mutations in the ANKRD26 coding region are less common but also induce ANKRD26 overexpression through a mechanism independent of RUNX1/FLI1 interaction. 43 The incidence of myeloid neoplasm in ANKD26 related individuals is higher, with an estimated 24-fold increased risk for developing AML compared with the general population.…”

“…41,43 Mutations in the ANKRD26 coding region are less common but also induce ANKRD26 overexpression through a mechanism independent of RUNX1/FLI1 interaction. 43 The incidence of myeloid neoplasm in ANKD26 related individuals is higher, with an estimated 24-fold increased risk for developing AML compared with the general population. 37 In a study of 118 subjects affected by ANKD26 mutation, 10 (8.4%) developed myeloid neoplasm, including 4 AML, 4 MDS, and 2 chronic myeloid leukemia.…”

Inherited thrombocytopenia and platelet disorders with germline predisposition to myeloid neoplasia

“…Most commonly described pathogenic variants are single nucleotide substitutions and small deletions located in the 5′ UTR of ANKRD26 that contains the transcription factor ( RUNX1 and FLI1 ) binding sites . A recent report with in vivo and in vitro functional studies suggests that N‐terminal truncated ANKRD26 isoforms have a strong ability to activate the MAPK/ERK signaling pathway that may lead to predisposition to a myeloid disorder …”