Open access journal of the Ferrata-Storti Foundation, a non-profit organization Open access journal of the Ferrata-Storti Foundation, a non-profit organization Department of Hematology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Department of Hematology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Department of Hematology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Department of Hematology, Beijing Chao-Yang Hospital, Capital Medical University,

In up to 25% of patients with acquired TTP, anti-ADAMTS13 antibodies are not identified, the mechanism resulting from ADAMTS13 deficiency remains unidentified (uTTP). In this study, we provide further insights on clinical presentation and outcome of uTTP. In patients with baseline undetectable anti-ADAMTS13 antibodies, usual features of iTTP (young age, cerebral involvement, severe thrombocytopenia) with no other associated context than a history of systemic autoimmune disease or pregnancy, should prompt to consider the diagnosis of iTTP.

Multiple myeloma (MM) patients are often refractory to targeted therapies including proteasome inhibitors. Here, analysis of RNA sequencing data derived from 672 patients with newly diagnosed or relapsed/refractory disease identified the acid ceramidase, ASAH1, as a key regulator of resistance to proteasome inhibitors. Genetic or pharmacological blockade of ASAH1 remarkably restored sensitivity to proteasome inhibitors and protected mice from resistant MM progression in vivo. Mechanistically, ASAH1 depletion of ceramide promoted SET inhibition of PP2A phosphatase activity, thus facilitating increased expression and activity of the pro-survival proteins, MCL-1 and BCL-2. We corroborated these findings in human MM datasets, and in ex vivo patients’ MM cells. These preclinical studies suggest that ASAH1 may be a potential therapeutic target for the treatment of relapsed/refractory MM.

Acute myeloid leukemia (AML) remains challenging to treat, which in part relates to genetic heterogeneity of the disease, to the protective tumor microenvironment driving resistance to therapy, and also to immune evasion characteristics of leukemic cells. Targeting epigenetic programs in AML provides an attractive opportunity to impair long-term proliferation and induce differentiation. The novel inhibitor JNJ-75276617 (bleximenib) targets the menin-KMT2A interaction and has shown preclinical efficacy in AML.1 Here, we provide mechanistic insights into how JNJ-75276617 impairs proliferation and drives differentiation of primary AML patient cells. A large-scale drug screen was set up in which genetic alterations and quantitative proteomics were compared with drug sensitivity in a preclinical setting, which revealed that granulocyte-macrophage progenitor (GMP)-like AML display the greatest sensitivity. Furthermore, we identified that NPM1c/DNMT3Amut AML are sensitive, and some NPM1wt AML