Issue Archive

In this Blood Spotlight, Chakraverty and Teshima shed light on the interplay between graft-versus-host-disease and tissue repair. They highlight the need and opportunities for new therapies that are both less immunosuppressive and more supportive of end-organ regeneration.

The role of allogeneic stem cell transplantation in adults with inborn errors of immunity (IEIs) manifesting as primary immunodeficiencies and autoinflammatory syndromes is increasingly recognized. However, numbers of patients who receive transplants are limited and counseling adult IEI patients remains challenging. This How I Treat article by Burns and Morris provides important information and substantial guidance about how to manage this process.

As gene therapy for severe hemophilia B advances through phase 3 trials and toward potential regulatory approval, issues around value and willingness to pay for curative therapy become important. Bolous and colleagues report a cost-effectiveness analysis comparing gene therapy to prophylaxis with standard and extended half-life factor IX products in the context of the US health system. Encompassing scenarios and assumptions about long-term efficacy and pricing that are also relevant in other countries, they suggest that gene therapy may be the most cost-effective strategy.

KRAS is the most frequently mutated gene in both newly diagnosed and relapsed multiple myeloma. Sacco et al demonstrate that while KRAS mutational status is not associated with survival, KRAS expression is negatively prognostic. AZD4785, a novel antisense oligonucleotide, reduces KRAS expression and inhibits myeloma cell growth both in vitro and in vivo, confirming that KRAS is both a driver of myeloma and a therapeutic target.

Prior studies using restricted genomic analyses did not indicate a link between acquired resistance to the immunomodulatory drug (IMiD) lenalidomide (LEN) and promoter methylation of cereblon (CRBN), the gene encoding its target. Using more complete genomic studies of CD38-purified cells from patients with myeloma and normal controls, Haertle et al identified that DNA hypermethylation of an intronic CRBN enhancer region downregulates CRBN expression and mediates LEN resistance in advanced myeloma, enhancing our understanding of acquired drug resistance in these patients.

Tanaka and colleagues build on our understanding of the clinical implications of clonal hematopoiesis (CH) after induction chemotherapy for acute myeloid leukemia. They demonstrate that CH is common and that beyond initial recovery it is associated with normal blood counts. CH persists in most patients despite various postremission therapies, with only allogeneic transplantation leading to its eradication.

Transcriptional control of terminal erythroid gene expression is implicated in many different hematopoietic disease states. Murphy and colleagues reveal that dynamic, maturation stage–specific changes in RNA polymerase II activity, regulated by HEXIM1, are essential for erythroid gene expression. These insights help explain how gene expression is regulated without the accumulation of heterochromatin in maturing erythroid cells.

Xu et al report development of a preclinical model for anti-CD36–mediated fetal/neonatal alloimmune thrombocytopenia (FNAIT), the leading cause of FNAIT in Asian and African populations. They provide novel insights into the pathogenic effect of maternal anti-CD36 antibodies and demonstrate preclinically that prenatal maternal immunotherapy using either polyclonal or monoclonal murine anti-CD36 antibodies is superior to human IV immunoglobulin treatment in preventing FNAIT, heralding a potential new approach to this clinical problem.

Astolf et al provide the first report of acute promyelocytic leukemia driven by viral insertion into the RARA locus. This represents a clear demonstration of a pathology driven by the member of the anelloviruses, a group of viruses otherwise thought to have minimal or no pathogenic potential.