Issue Archive

Single-cell profiling technologies can assess the genome, transcriptome, and epigenome of individual cells at high resolution. When combined, they allow recognition of cell identity, state, and activity. Samur and colleagues review how these technical and bioinformatic advances have shed light on how myeloma can become drug-resistant and the nature of the bidirectional relationship between clonal evolution and the changing tumor microenvironment.

Immune thrombotic thrombocytopenic purpura (iTTP) can cause small vessel ischemic damage to any organ, including the brain. Chaturvedi and colleagues document silent cerebral infarction (SCI) in 50% of patients with iTTP in remission studied prospectively with MRIs and cognitive tests. SCI is strongly associated with major cognitive impairment, even in patients who had no overt neurological event during their acute episode.

Structural variants (SVs) are large sequence differences from normal genomes and occur commonly in leukemias and other cancers. Botten et al describe a new approach that combines genome sequencing, chromatin state, and transcriptional signatures to distinguish pathogenic SVs driving leukemogenesis from nonpathogenic passenger events. The authors identify methylation as a barrier to enhancer hijacking–mediated oncogenic transcription arising from SVs and demonstrate the applicability of their tools and model (Orca-Leukemia) in primary samples.

Aggressive natural killer cell leukemia (ANKL) is a rare hematological malignancy characterized by an aggressive clinical course and very poor prognosis. To study its pathophysiology, Kameda et al used patient-derived xenografts to mimic leukemic infiltration into hematopoietic organs, revealing the hepatic sinusoids to be a favored niche. The authors identified the transferrin–transferrin receptor 1 (TfR1) interaction as pivotal to this and demonstrate that an anti-TfR1 antibody has therapeutic potential in this model.

Shao and colleagues reveal that a palmitoyltransferase, zinc finger DHHC-type containing 21 (ZDHHC21), regulates oxidative phosphorylation and is essential for a subset of acute myeloid leukemia (AML) cells in preclinical models. The authors’ work maps how palmitoylation of protein substrates by ZDHHC21 influences mitochondrial function and highlights ZDHHC21 as a potential druggable therapeutic target in AML.

Sickle cell disease (SCD) is characterized by hemolysis, systemic hypoxia, and elevated oxidative stress. Xi and colleagues uncover how the transcription factor Nrf2, a master regulator of cellular oxidative response, alters l-2-hydroxyglutarate–mediated histone methylation and consequently reactive oxygen species production and ferroptosis in erythroblasts. Pharmacological activation of Nrf2 in murine SCD models protects against oxidative damage and ferroptosis, reducing hemolysis in vivo. These data suggest Nrf2 is a potential therapeutic target to ameliorate SCD symptoms.