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Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome/exome and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains/amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains/amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL.

Summary.In previous studies, we demonstrated an overexpression of the dominant-negative isoform of the transcription factor Ikaros, Ik-6, in patients with B-cell malignancies, including blast crisis of chronic myelogenous leukaemia and acute lymphoblastic leukaemia. To investigate the consequence of over-expression of Ik-6 in B cells, we constructed Ik-6 transfectants of the FDH-1 and Ramos cell lines. FDH-1, which was established from a patient with early pre-B acute lymphoblastic leukaemia, undergoes apoptosis with dexamethasone treatment, whereas Ramos undergoes apoptosis following anti-IgM antibody treatment.Compared with the wild type, the over-expression of Ik-6 rendered the FDH-1 and Ramos transfectants resistant to dexamethasone-induced and anti-IgM-induced apoptosis respectively. An immunoblotting study demonstrated bcl-2 upregulation in anti-IgM-induced Ramos Ik-6 transfectants, but not in FDH-1 Ik-6 transfectants. Further investigations of the mechanism of leukaemogenesis associated with the over-expression of Ik-6 are warranted.

We report successful treatment by bone marrow transplantation (BMT) in an acute myeloid leukemia (AML) patient with Glanzmann thrombasthenia (GT). Genetic analysis revealed that a novel point mutation in exon 3 of the GPIIb gene led to abnormal splicing resulting in an amino acid substitution and an in-frame deletion of 3 amino acid residues. Expression studies suggested a rapid degradation of the uncomplexed protein within the cells. Induction therapy for AML was performed with frequent platelet transfusions because of the patient's severe hemorrhagic manifestations. In the second remission, the patient was successfully treated by BMT from an HLA-matched unrelated donor. Platelet function returned to normal, and the GT phenotype completely disappeared. Our experience suggests that BMT is a curative therapeutic strategy for GT. Furthermore, we believe this study is the first to demonstrate that engraftment after BMT for AML can be determined by monitoring the congenital genetic defect of GT.