Additional molecular aberrations leading to leukemic transformation in patients with familial platelet disorder.

NICOLAS DUPLOYEZ ; ILÉANA ANTONY-DEBRÉ; MAXIME BUCCI; SANDRINE GEFFROY; NICOLAS BOISSEL; CÉLINE BERTHON; NATHALIE DHÉDIN; THIERRY LEBLANC; DELPHINE RÉA; PAULA G HELLER; RÉMI FAVIER; VÉRONIQUE LATGER-CANNARD; MARIE-JOËLLE MOZZICONACCI; BRIGITTE NELKEN; HANA RASLOVA; CLAUDE PREUDHOMME

Congreso; 20th Congress of the European Hematology Association; 2015

BackgroundFamilial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) is a rare autosomal dominant disorder characterized by quantitative and qualitative platelet abnormalities and considered as a model of genetic predisposition to hematological malignancies. FPD/AML syndrome is caused by inherited RUNX1 mutations (21q22) reported so far in less than 40 pedigrees. However, evolution remained very heterogeneous since only 30-40% of such patients develop hematopoietic neoplasms, usually after a long period.AimsIn this context, it is likely that the acquisition of secondary molecular events functions as a driver to promote malignant transformation, thus the FPD/AML syndrome constitutes a unique multi-step leukemogenesis model in vivo. Recently, acquired mutations of CDC25C and GATA2 have been reported in 53% and 23% of FPD/AML patients respectively (Yoshimi et al, Nat Commun, 2014), particularly during disease progression.MethodsWe studied 24 patients from 15 FPD/AML families identified from 2005 to 2014. Twelve of them progressed to leukemic stage: 9 patients developed AML and 3 patients developed T-ALL. Cytogenetics and next-generation sequencing (MiSeq, Illumina®) of 44 genes (including CDC25C and GATA2) were performed for all patients. For patients who progressed to leukemic stage, samples were collected at the time of diagnosis and during complete remission allowing to confirm the acquired status of mutations.ResultsCharacteristics of the patients studied are presented in the following table:SummaryAcquisition of a secondary genetic or molecular event was identified in all patients of our cohort. Acquired mutations involved genes implicated in tyrosine kinase pathway, epigenetic, spliceosome and transcription regulation. In addition to germline RUNX1 mutation, a second aberration of RUNX1 was found in all patients who developed AML, in line with our previous report (Preudhomme et al, Blood, 2009). Four patients acquired mutation in the second allele and 4 patients had duplication of the abnormal copy by uniparental disomy (n=2) or acquired trisomy 21 (n=2). On the other hand, patients who developed T-ALL were younger and did not acquire second aberration of RUNX1. Interestingly, CDC25C or GATA2mutations were not identified in our cohort, in contrast with Yoshimi et al.