Myeloid malignancies with acquired trisomy 21 as the sole cytogenetic change are clinically highly variable and display a heterogeneous pattern of copy number alterations and mutations *

Objectives:  Acquired trisomy 21 is one of the most common numerical abnormalities in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), and MDS/MPN; however, little is known about its pathogenic impact, accompanying submicroscopic changes, and its relation to other clinical features. Furthermore, previous studies addressing this issue have mainly focused on cases in which +21 was part of a complex karyotype. Methods:  We ascertained the incidence of +21, both as a sole change (T21s) and irrespective of additional changes (T21all), in relation to disease type, morphologic subgroup, gender, and age in all published AML, MDS, MPN, and MDS/MPN cases. Furthermore, single nucleotide polymorphism (SNP) array analysis was performed on 11 myeloid malignancies with T21s, followed by mutation analysis of the FGFR1 , FLT3 , GATA1 , JAK2 , KIT , NPM1 , NRAS , RUNX1 , and TET2 genes. Results:  The frequencies of T21s and/or T21all varied significantly among the AML, MDS, MPN, and MDS/MPN cases, among the AML and MPN subtypes, and in relation to the age of the AML, MDS, and MPN patients. In the 11 cases analyzed by SNP array, a total of nine genomic imbalances, comprising seven deletions and two duplications, were identified in six cases; none of the alterations were recurrent. Partial uniparental disomies (UPDs) were found in five cases; two recurrent UPDs were identified, namely UPD4q and UPD7q. Mutations in NPM1 , RUNX1 , and TET2 were detected in five cases, three of which harbored a pathogenic RUNX1 mutation. The TET2 mutation was found in one of the cases with UPD4q. Conclusions:  The results show that trisomy 21‐positive myeloid malignancies are clinically highly variable and that they display a heterogeneous pattern of copy number alterations and mutations.