Issue Archive

There are now multiple Bruton tyrosine kinase (BTK) inhibitors available, all sharing the common mechanism of blocking enzymatic activity, while exhibiting minor differences in efficacy, toxicity, and mechanisms of resistance. Tam and colleagues succinctly summarize emerging data on specific differences in how chronic lymphocytic leukemia (CLL) can evade each of the agents in this timely Blood Spotlight. The authors put the implications of this new knowledge in context for current practice, where sequential use is increasing, as well as for trial design and research into drugs that act by degrading BTK.

While T cells are central to the activity of allogeneic stem cell transplant, chimeric antigen receptor T-cell therapy, and many bispecific antibodies against hematological malignancies, other hematopoietic cells play important roles in modulating responses. Adams and colleagues review understanding of the ontogeny, function, and contributions of monocytes and macrophages to clinical outcomes with these immunotherapies. The authors further discuss how newly available agents targeting these cells can be used for therapeutic advantage.

CD7 is a T- and natural killer–lineage marker that is expressed in a minority of acute myeloid leukemias, especially less differentiated subtypes. Lu et al report initial results from a small phase 1 study of autologous CD7 chimeric antigen receptor (CAR)–modified T cells in heavily pretreated patients, finding that this approach is highly effective at inducing remission, even after previous allogeneic transplant. While durability of remissions remains a challenge, these data do encourage further pursuit of CD7 as a target for immunotherapy.

A subset of hematopoietic stem cells (HSCs) is lineage-primed and can rapidly expand to generate megakaryocytes upon challenge with proinflammatory factors. Kauppi and colleagues shed light on the molecular regulation of these cells, identifying that the scaffolding protein cullin-5 functions as a negative regulator of megakaryocyte-biased progenitors within the HSC pool. Surprisingly, this is mediated not by regulation of thrombopoietin or interferon signaling, but rather through modulation of interleukin-3 and related cytokines.

A mutation resulting in a leucine-to-proline change at position 265 of the myeloid differentiation primary response protein 88 (MYD88 L265P) is commonly found in subtypes of diffuse large B-cell lymphomas, where it instigates a constitutive survival stimulus. Li et al report that lasalocid A, a candidate small molecule compound identified in a high throughput screen, selectively targets and degrades the mutated protein, reversing ibrutinib resistance and exhibiting synergistic activity with venetoclax. This preclinical study validates the MYD88 L265P protein as a promising target and supports the clinical development of degraders like lasalocid A.

The French National Histiocytosis Registry has been established for over 40 years, enabling longitudinal study of rare entities such as subtypes of Langerhans cell histiocytosis in childhood where there is hematological compromise. Thalhammer and colleagues describe features indicating that this is a life-threatening condition that is strongly associated with the BRAF^V600E mutation. Based on improved trends in survival since the availability of MAPK inhibitors, the authors recommend early commencement of targeted therapy.

Exploiting whole genome sequencing data from >1000 patients with β-thalassemia, Long and colleagues discovered that missense mutations in autophagy and beclin 1 regulator 1 (AMBRA1) were associated with increased severity of phenotype. In β-thalassemic mice, human erythroid cells, and CD34⁺ hematopoietic progenitor cells, the authors demonstrate that AMBRA1, an E3 ubiquitin ligase, functions to stimulate the autophagy of free α-globin. When AMBRA1 mutations reduce their activity, the imbalance between α-globin and β-globin increases, causing exacerbation of defective erythropoiesis.

Exposure to air pollution is increasingly common. Lutsey et al report on data from a cohort of 6651 participants, recruited when healthy and prospectively studied for up to 17 years, across 6 regions in the United States where air pollution was measured fortnightly. After controlling for known risk factors, the authors identified a marked association between greater air pollution and higher risk of venous thromboembolism (VTE). The elevated risk is approximately 5-fold within 10 years for VTE unrelated to cancer, prompting the need for studies to investigate the underlying mechanism and strengthening arguments for better control of air pollution.