- Review Series: mechanisms and clinical implications of clonal hematopoiesis
- Erythrocyte clearance in the spleen is mediated by adhesion-induced hemolysis
- Tandem CD19/20 CAR T cells for relapsed/refractory B-cell lymphoma
- HHEX cooperates with mutant ASXL1 to promote myeloid leukemia
- Crystal structure of the contact system complexed to globular C1q receptor
In this week’s episode, we will learn more about the role of hepcidin in fetal iron homeostasis, review a new study with improved outcomes in HLA-antigen mismatched transplantation, and examine how two splicing factor mutations can coexist in the same cell in patients with myeloid malignancies.
Single-cell genomics reveals the genetic and molecular bases for escape from mutational epistasis in myeloid neoplasms
Conventional wisdom has it that cooccurrence of mutations in 2 RNA splicing factors in the same cell is lethal for cells. Taylor and colleagues used single-cell analysis to reveal that while this is generally true, concurrent pathogenic mutations in 2 such genes can occur, being observed in rare cases (<0.5%) of myeloid neoplasia. In a Plenary Paper, they reconcile this conundrum by showing that allele-specific differences in the degree of altered function account for whether splicing factor mutations can cooccur or must exist exclusively.
Arginine, the substrate for nitric oxide production, is deficient in patients with sickle cell vaso-occlusive crisis. Morris et al report improved markers of oxidant stress and mitochondrial stress in platelet-rich plasma from 12 patients treated with intravenous arginine, suggesting that arginine may offer a potential therapeutic intervention for sickle crisis.
Sirolimus with CSP and MMF as GVHD prophylaxis for allogeneic transplantation with HLA antigen–mismatched donors
High levels of acute graft-versus-host-disease (aGVHD) are a barrier to use of donors mismatched at class I or II human leukocyte antigen (HLA) loci for allogeneic hematopoietic stem cell transplantation. Kornblit et al report that in a large phase 2 trial, the addition of sirolimus to standard GVHD prophylaxis achieved lower rates of severe aGVHD and improved overall survival in comparison with historical controls.
Raffel et al report key proteome and transcriptome data sets for functionally characterized normal and leukemic hematopoietic stem cells. These investigations identify characteristic and targetable pathways active in leukemic stem cells compared to their normal counterparts, including in metabolic pathways that are particularly evident at the protein level.
Macrophage metabolic adaptation to heme detoxification involves CO-dependent activation of the pentose phosphate pathway
In preclinical studies including a murine model of sickle cell disease, Bories and colleagues uncovered a metabolic shift in macrophages involved in clearing free heme. This shift maintains redox homeostasis in macrophages. The data suggest that pharmacological modulation of this metabolic adaption may be a way to minimize the toxic effects of free heme in a variety of hematological disorders.