Mutations responsible for ANKRD26-related thrombocytopenia increase the risk of hematological malignancies but are not frequently involved in de novo acute leukemias

BALDUINI CARLO L; YU G; HELLER PG; ALESSI MC; GIORDANO P; KUNISHIMA S; BUSSEL J; VIANELLI N; NIEDERHOFFER N; PODDA GIAN MARCO; SAGLIO G; MARTA ROSANA FINELLI G; NORIS P; SAVOIA ANNA; SERI M; FAVIER R

Estocolmo

Congreso; 18th Congress of the European Hematology Association; 2013

European Hematology Association

Background: It has been recently shown that mutations in the 5’UTR of ANKRD26 result in an autosomal dominant form of thrombocytopenia with normal size platelets that has been named ANKRD26-Related Thrombocytopenia (ANKRD26-RT) ( Am J Hum Genet 2011;88:115-20). Gene overexpression seems to be the consequence of mutations. It has been suggested that ANKRD26-RT is one of the less rare forms of inherited thrombocytopenias in that it was identified in 21 of 210 families with genetically transmitted low platelet counts (Blood 2011;117:6673-80). Analysis of 78 patients revealed that thrombocytopenia and bleeding tendency were usually mild or moderate, and bone marrow examination suggested that thrombocytopenia was derived from dysmegakaryopoiesis. Unexplained high values of hemoglobin and leukocytes were observed in some cases. The most important clinical remark of ANKRD26-RT was the association with acute leukemia, which affected 6% of patients. Aims: The purpose of this study was to confirm the clinical and laboratory characteristics of ANKRD26-RT that have been identified in the first case series of patients. In particular, we wanted to confirm that the disease increases the risk of hematological malignancies. Moreover, we wanted to ascertain whether the 5 ´UTR of ANKRD26 is mutated in de novo acute leukemias. Methods: We searched for mutations in the 5’UTR of ANKRD26 in patients with inherited thrombocytopenias who had remained without a definite diagnosis at the end of the diagnostic procedure. The search for mutations in the 5’UTR of ANKRD26 was also performed in 254 subjects with acute leukemia. Results: We identified 11 heterozygous single nucleotide substitutions and 1 small deletion in the 5’UTR of ANKRD26 in 65 patients from 21 pedigrees with inherited thrombocytopenia. Four of these mutations (c.-116C>G, c.-126T>C, c.-127delAT, c.-128G>C) had not been detected previously. Bleeding tendency was mild (most patients with grade 1 or 2 of the WHO bleeding scale), platelet count was moderately reduced (mean value/SD: 51/29 x109/L) and mean platelet volume was usually normal (mean value/SD: 9/2 fL). Hemoglobin and leukocyte levels higher than normal were observed in 5 and 13 cases, respectively. Considering also 27 affected family members who died before our study, the extended series of 92 patients includes 6 subjects with AL, 3 with myelodysplastic syndrome (MDS) and 2 with chronic myelogenous leukemia (CML). Mutation screening in patients with de novo acute leukemias identified mutations in the 5’UTR of ANKRD26 in one subject. However, medical history revealed that he was thrombocytopenic before developing leukemia and that other family members were known to be affected by ANKRD26-RT. Summary / Conclusion: Our study brings the number of families with ANKRD26-RD described in the literature to 42 and makes this form of inherited thrombocytopenia one of the most frequently reported. Analysis of this new case series confirmed that the typical picture of ANKRD26-RT is that of an autosomal dominant disorder characterized by moderate thrombocytopenia with normal sized platelets and mild bleeding diathesis. It also confirmed that mutations in 5’UTR of ANKRD26 predispose to hematological malignancies, in that 11 of 92 affected subjects developed AL, MDS or CML. However, our study excluded that these mutations are frequently involved in de novo AL.