A 58-year old male patient was referred to our department due to normocytic anemia and leucopenia in May 2008. His anamnesis included mild diabetes type II and solitary congenital kidney with normal renal function, and he was on no medication. A complete blood count performed a year ago was showing hemoglobin (Hb) 121 g/L and average leukocyte count (WBC) and platelet counts. The patient was in relatively good condition complaining only of mild fatigue, and the physical examination was unremarkable. Haemoglobin was 74 g/L, platelets 165 x 109/L, MCV 83 fl, WBC 2.98 x 109/L and the absolute neutrophil count (ANC) 1.4 x 109/L, while biochemistry, including LDH, was normal. The rest laboratory workup revealed erythropoietin serum level of 19.6 IU/L (normal range 3.3-24.4 IU/L), ferritin levels 418 ng/dl and B12 levels 1166 pg/ml. The blood film showed dimorphic red cells, and hypogranular neutrophils with ringed nuclei (Figure 1a) and the bone marrow aspirate was consistent with refractory anaemia with multilineage dysplasia, and 40% ringed sideroblasts (RCMD-RS). Blast count was 1%. Bone marrow biopsy also revealed a hypercellular marrow with trilineage dysplasia and grade I reticulin fibrosis by Gomori's silver stain. Cytogenetic studies were performed in bone marrow by using conventional G-banding analysis and showed 12/20 metaphases carrying the 46, XY, i(17q)(q10) and 8/20 residual normal metaphases. By using PCR we found mutations in SETBP1, U2AF1 and KIT genes, whereas no mutations were found in SF3B1, JAK2, MPL, CALR, IDH1, IDH2, DNMT3A, SRSF2 and ASXL1 and no chimeric transcripts of BCR/ABL were detected. The patient was transfused and started on recombinant erythropoietin (EPO) at 40.000 IU/week. Two months after, Hb was 87 g/l, and we doubled the EPO dose at 80.000IU/week. He remained untransfused for 7 months when his Hb rose at 112 g/L, and although EPO was reduced to 40.000 IU/week, after 3 months the Hb levels reached 140 g/L, and EPO was discontinued. He did not receive further EPO for 12 months, being asymptomatic with normal Hb levels, whereas due to a synchronous rise in WBC and platelet counts we performed JAK2V617F mutation analysis with negative results. However, 24 months after diagnosis the patient developed splenomegaly 5cm below left costal margin and low-grade fever peaking in the afternoon. His Hb dropped at 84 g/L, his platelet count at 103 x 109/L and the WBC rose to 21.7 x 109/L. Peripheral blood smear showed 9% blasts, and immunophenotypic analysis by 4-color flow cytometry demonstrated a CD45low population with typical myeloblast phenotype, positive for CD34, CD117, CD33, HLA-DR and CD13, and negative for CD15, CD19, CD10, CD56, CD7 and CD61 (Figure 1b). The aspirate was unsuccessful (dry tap) and the bone marrow biopsy showed a hypercellular marrow with myeloid and megakaryocytic hyperplasia, decreased erythropoiesis, 9% blasts, and reticulin fibrosis grade 2-3, whereas low-grade collagen fibrosis was also present. A new cytogenetic study was pursued and, unexpectedly, revealed a regular 46, XY[30] karyotype and normal FISH findings (Supplemental Figure S1), whereas his mutational profile remained unchanged. The patient received 5 courses of subcutaneous azacytidine at 75 mg/m2 for seven days on 28-day cycles, but his splenomegaly progressed, and along with the ongoing fever he developed night sweats and weight loss. We administered induction chemotherapy with cytarabine (Ara-C) 100g/m2/d iv d1-7 and idarubicin 12 mg/m2/d iv d1-3, but the patient succumbed to sepsis after 23 days. The course of the patient's CBC is shown in Figure 1c.