Blood最新文献

Abstract: Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the (oligo)clonal expansion of myeloid progenitor cells. Despite advances in treatment, AML remains challenging to cure, particularly in patients with specific genetic abnormalities. Menin inhibitors have emerged as a promising therapeutic approach, targeting key genetic drivers of AML, such as KMT2A (lysine methyl transferase 2A) rearrangements and NPM1 mutations. Here, we review the clinical value of menin inhibitors, highlighting their mechanism of action, efficacy, safety, and potential to transform AML treatment.

Abstract: Rising blast percentage or secondary acute myeloid leukemia (sAML) transformation in myeloproliferative neoplasms (MPNs) leads to JAK1/2 inhibitor (JAKi) therapy resistance and poor survival. Here, we demonstrate that treatment with the CDK7 inhibitor (CDK7i) SY-5609 depletes phenotypically characterized post-MPN sAML stem/progenitor cells. In cultured post-MPN sAML SET2, HEL and patient-derived (PD) post-MPN sAML cells, SY-5609 treatment inhibited growth and induced lethality while sparing normal cells. RNA-sequencing analysis after SY-5609 treatment reduced mRNA expression of MYC, MYB, CDK4/6, PIM1, and CCND1 but increased expression of CDKN1A and BCL2L1. Mass spectrometry of SY-5609-treated MPN-sAML cells also reduced c-Myc, c-Myb, PIM1, and CDK4/6 but increased p21, caspase-9, and BAD protein levels. CRISPR-mediated CDK7 depletion also reduced cell viability of HEL cells. Cytometry by time of flight (CyTOF) analysis of SY-5609-treated PD post-MPN sAML stem/progenitor cells showed reduced c-Myc, CDK6, and PU.1 but increased protein levels of CD11b, p21, and cleaved caspase-3. Cotreatment with SY-5609 and ruxolitinib was synergistically lethal in HEL, SET2, and PD post-MPN sAML cells. A CRISPR screen in sAML cells revealed BRD4, CBP, and p300 as codependencies with CDK7i. Accordingly, cotreatment with SY-5609 and the bromodomain and extra-terminal protein inhibitor (BETi) OTX015 or pelabresib or the CBP/p300 inhibitor GNE-049 was synergistically lethal in MPN-sAML cells (including those exhibiting TP53 loss). Finally, in the HEL-Luc/GFP xenograft model, compared with each agent alone, cotreatment with SY-5609 and OTX015 reduced sAML burden and improved survival without host toxicity. These findings demonstrate promising preclinical activity of CDK7i-based combinations with BETi or CBP/p300 inhibitor against advanced MPNs, including post-MPN sAML.

The last decade has seen the introduction of two new licensed therapies for thrombotic thrombocytopenic purpura (TTP)-caplacizumab and recombinant ADAMTS 13 (rADAMTS 13), for immune (iTTP) and congenital TTP (cTTP) respectively. They improve acute TTP outcomes, reduce the need for plasma therapy, time to clinical response and treatment burden. Future pathways need to replace plasma exchange in acute TTP and optimise/personalise rADAMTS 13 in cTTP. Future emphasis should focus on additional monoclonals/treatments to tackle ADAMTS 13 antibodies.

Abstract: We identified 347 pregnancies in patients with β-thalassemia minor. Hemoglobin was <9 g/dL in 31% during third trimester and 7.6% at delivery. Postpartum hemorrhage occurred in 8.9%. Forty-six percent of IV iron administration was to iron-replete patients.

Differentiation arrest and dependence on oxidative metabolism are features shared among genetically diverse acute myeloid leukemias (AML). A phenotypic CRISPR-Cas9 screen in AML identified dependence on phosphoseryl-tRNA kinase (PSTK), an atypical kinase required for the biosynthesis of all selenoproteins. In vivo, PSTK inhibition (PSTKi) impaired AML cell growth and leukemic stem cell self-renewal. Notably, timed pharmacologic PSTKi effectively targeted chemo-resistant AML in murine and patient-derived xenograft models, showing selectivity for malignant cells over normal hematopoietic cells. Mechanistically, PSTKi-induced reactive oxygen species (ROS) triggering mitochondrial DNA release into the cytosol and activated cGAS-STING. This activation in turn disrupted iron metabolism augmenting ROS generation and amplifying ferroptosis. Together, these findings reveal a self-reinforcing PSTK-cGAS-STING-ROS loop culminating in an oxidative crisis and ferroptotic cell death of leukemic stem cells. The data highlight the potential for augmenting standard cancer chemotherapies using timed metabolic intervention to eliminate chemopersisting cells and thereby impede disease relapse.