Octasomy 21 in a patient with secondary AML after CMML: the role of acquired NRAS mutations in triggering aneuploidy

CMML is an aggressive form of myeloid neoplasia with features of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) characterized by peripheral monocytosis and bone marrow dysplasia. Therapeutic options are limited. Median survival is 24 months [1]. The prognostic risk score comprises the variables BM blasts, WBC count, RBC transfusion dependency as well as the genetic risk groups. The latter is categorized according to the cytogenetic risk group as well as mutational status of ASXL1, NRAS, RUNX1 and SETBP1 [2]. Acute myeloid leukaemia (AML) arising from chronic myelomonocytic leukaemia (CMML) is usually associated with a poor prognosis and occurs in 10–30% of cases [3,4]. Around 55% of these transformed cases, show a normal karyotype and a pathogenic NPM1 variant can be detected in 17%. Median survival is 6 months, and with this, similar to AML secondary to MDS [3]. Karyotypic abnormalities characteristically comprise AML-associated aberrations including trisomy 8, monosomy 7, deletions of part of the long arm of chromosome 7, structural abnormalities of the short arm of chromosome 12 and complex karyotypes [4]. We, here, describe a 72-year-old-male patient who was diagnosed with a cytogenetically normal CMML-1. No molecular genetic analyzes were performed at first diagnosis. He was treated with G-CSF and erythropoietin. Cytogenetic analysis on blood cells still showed a normal karyotype. The pathogenic JAK2 variant c.1849G> T; p.V617F was positive. At the age of 80 years (99 months after initial diagnosis), a secondary AML was diagnosed. The blast count was 60% with early myeloid differentiation and multilineage dysplasia. At that time a hyperdiploid karyotype with—among other numerical aberrations—an octasomy of the chromosome 21 was detected (54,XY,þ13,þ19,þ21,þ21,þ21,þ21,þ21,þ21[14]/ 46,XY[1]) (Figure 1(A)). Treatment with azacitidine was started, but he died 2 months after the diagnosis of secondary AML (101 months after initial diagnosis of CMML). In addition to our case, we found one case of secondary AML and a hyperdiploid karyotype (trisomy 13 and 15) after a cytogenetically normal CMML with an overall survival of 5 months after diagnosis of AML he had a particularly poor outcome [4]. The patient from that case report survived for additional 2 months after diagnosis of a secondary AML. With respect to that case, and the disease history of our patient with an octasomy 21, we speculate that these karyotypic abnormalities are associated with an extremely adverse outcome. Keeping in mind, that AML with an aneuploidy of chromosome 21 or chromosome 8 is generally associated with an intermediate prognosis [5], larger studies will have to shed light on this speculation that will have impact for the patients. Furthermore, the detection of octasomy of chromosome 21 raised the question of the potential genetic trigger of this the very rare cytogenetic aberration during progression of the disease. As RUNX1 is located on chromosome 21. RUNX1 mutations are prognostically relevant in myeloid leukemia and are causative for a subtype of familial leukemia. It was our interest to investigate this patient on the genetic level [6]. We, therefore, performed retrospective analysis of the patient via array CGH analysis and a mutational hotspot analysis using the Illumina TruSight Myeloid Sequencing Panel (Illumina, San Diego, CA). Mutational hotspot analysis could be performed on DNA from bone marrow cells obtained after stimulated cell culture 64 months after initial diagnosis as well as on DNA from fresh bone marrow cells 99 months after initial diagnosis. Unfortunately, this was not possible at the time point of diagnosis because of low DNA quality. Array CGH analysis could only be performed on material of the last time point (Supplementary data). NGS panel analysis during the course of the CMML revealed the known pathogenic variant in JAK2 and three further pathogenic variants in TET2 [c.5618T>C;