Issue Archive

Human T-cell leukemia virus type I (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL) in 5% of infected people with a decades-long latency. Charles R. M. Bangham reviews the basis for viral persistence and the molecular events of driver mutation acquisition and immune evasion that lead to the emergence of ATL.

Neelapu et al report on a 5-year follow-up of the ZUMA-1 trial of axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor T-cell therapy for refractory large B-cell lymphoma (LBCL) and confirm sustained response in those achieving complete response. At 5 years, 31% of treated patients had sustained responses, with an overall 5-year survival of 42.6%, increasing the probability that axi-cel has curative potential for a subset of patients with refractory aggressive LBCL.

In a novel gene therapy approach, Calabria et al delivered adeno-associated virus vectors (AAVs) by direct injection into mouse thymus in vivo and demonstrate that over 90% of the transgene integration sites were within T-cell receptor (TCR) gene loci. Integration occurs through exploitation of TCR gene rearrangement during variable, diversity, and joining segment rearrangement through the activity of recombination activation genes. Whether this can be translated into human gene therapy remains to be established.

Familial hemophagocytic lymphohistiocytosis (fHLH) is a severe immunoregulatory disease arising from biallelic loss-of-function mutations in genes necessary for normal T-cell and natural killer cell cytotoxicity. Noori and colleagues address the vexing issue of the activity of variants of uncertain significance (VUS) in known fHLH genes. The authors describe a novel cell-based system for characterizing VUS by transfecting them into murine CD8 cells that have a knockout of the cognate gene to determine if the human gene complements the functional defects. Though complex, this approach provides better diagnosis and pathogenetic insights into rare potentially pathogenic variants.

Classic Hodgkin lymphoma (cHL) is a unique tumor, with rare tumor cells embedded in a mix of immune cells that create an immunosuppressive microenvironment. Using molecular profiling, Stewart et al describe the complex microenvironment of cHL, characterizing the crosstalk between Reed-Sternberg cells and the surrounding monocytes, macrophages, and dendritic cells that lead to immune evasion.

Patients receiving cytotoxic chemotherapy and autologous transplantation may develop therapy-related myeloid neoplasms (tMN). Diamond and colleagues analyzed the genomic evolution of tMN to distinguish between chemotherapy-induced mutations and evolution from previous clonal hematopoiesis. tMN arising after mutagenic chemotherapy shows a complexity of new mutations, while tMN arising after nonmutagenic chemotherapy resembles de novo acute leukemia. The trajectory of tMN may arise from the acquisition of new mutations, selection of previously mutated clones, or the expansion of mutant clones transferred from the apheresis product.

Vekariya et al study the importance of formaldehyde accumulation in leukemia cells. Formaldehyde accumulates in leukemia cells and contributes to development of toxic DNA-protein crosslinks (DPCs). Leukemia cells depend on DNA polymerase θ (POLθ) to repair DPC-containing double-stranded breaks, and its downregulation decreases leukemia cell colony formation. Targeting POLθ may therefore be a promising clinical target in acute leukemia.

C1 inhibitor (C1INH) is a serine protease inhibitor that is a negative regulator of several pathways, including the contact pathway of coagulation. Congenital absence of C1INH is the major cause of hereditary angioedema (HAE). Grover et al report that patients with HAE have an increased risk of thrombosis, and in this follow-up study, the authors demonstrate that plasma from patients with HAE leads to increased contact-mediated thrombin generation. Furthermore, C1INH-deficient mice have increased venous thrombosis, which is reversible by C1INH administration.