Cytogenetically normal acute myeloid leukemias (CN-AML) represent about 50% of total adult AML. Despite the well-known prognosis role of gene mutations such as NPM1 mutations of FLT3 internal tandem duplication (FLT3-ITD), clinical outcomes remain heterogeneous in this subset of AML. Given the role of genomic instability in leukemogenesis, expression analysis of DNA repair genes might be relevant to sharpen prognosis evaluation in CN-AML. A publicly available gene expression profile dataset from two independent cohorts of patients with CN-AML were analyzed (GSE12417). We investigated the prognostic value of 175 genes involved in DNA repair. Among these genes, 23 were associated with a prognostic value. The prognostic information provided by these genes was summed in a DNA repair score, allowing to define a group of patients (n = 87; 53.7%) with poor median overall survival (OS) of 233 days (95% CI: 184–260). These results were confirmed in two validation cohorts. In multivariate Cox analysis, the DNA repair score, NPM1, and FLT3-ITD mutational status remained independent prognosis factors in CN-AML. Combining these parameters allowed the identification of three risk groups with different clinical outcomes in both training and validation cohorts. Combined with NPM1 and FLT3 mutational status, our GE-based DNA repair score might be used as a biomarker to predict outcomes for patients with CN-AML. DNA repair score has the potential to identify CN-AML patients whose tumor cells are dependent on specific DNA repair pathways to design new therapeutic avenues.

NK cells can play a significant role in the antitumoral immune response. In patients with acute myeloid leukemia (AML), NK cells are, however, often found in low numbers and exhibit poor activity, contributing to leukemic progression. Allogenic NK cells are emerging as promising cellular therapies for hematologic cancer treatment. New strategies are however required to both reactivate NK cells in patients with AML and enhance the antitumor activity of transplanted NK cells. In this study, we demonstrate that targeting SUMOylation, a protein posttranslational modification, activates NK cells from both healthy donors and patients with AML. Subasumstat (TAK-981), a first-in-class inhibitor of SUMOylation used in phase I/II clinical trials, enhances NK cell degranulation, secretion of inflammatory cytokines (IFN-γ, TNF-α, and FasL), and cytotoxicity against AML cells. In vivo, TAK-981 improves the anti-leukemic efficacy of ex vivo expanded cord blood NK cells in leukemia-bearing mice. One early effect of TAK-981 is to specifically increase the accessibility and activation of cis-regulatory regions of IFN-I pathway genes and induce their transcription. TAK-981–induced secretion of IFN-β, mostly by NK cells and myeloid cells, is required for NK cell activation. Surprisingly, IFNB1 induction does not require its best-characterized activators MDA5, cGas, and IFN response factor-1, -3, and -7. Altogether, this suggests that targeting SUMOylation activates a noncanonical IFN-I pathway, which enhances the anti-leukemic potential of NK cells.

We describe the case of a patient with extreme thrombocytosis whose evolution was rapidly fatal. No cause of secondary thrombocytosis was found. There was no sign of myelofibrosis but the megakaryocytes were small and dysplastic. The patient presented a calreticulin (CALR) variant in exon 3 (C105S), as well as concomitant mutations of ASXL1, U2AF1, and EZH2. This variant of CALR has never been described before, and after sorting, all identified mutations were found in myeloid cells but not in lymphoid cells. Therefore, the diagnosis of a frontier case of myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) was made. A treatment with hydroxycarbamide was started because of a high risk of thrombosis. Upon worsening of the hematological status two new mutations appeared, SETBP1 and ETV6, and the CALR mutation was still detectable, as well as the three other mutations found in the chronic stage. Our results show that this variant could contribute to MDS/MPN pathogenesis in that patient.