Issue Archive

Xie and Smith review the current understanding of the role of the microbiota and its diversity on responses to cellular therapies, including stem cell transplantation and chimeric antigen receptor (CAR) T cells. Although the mechanism is still to be determined, there is a complex interaction between the microbiota and the immune regulatory pathways governing response to cellular therapies. Loss of diversity of the microbiota is associated with a decreased response to transplantation and CAR T-cell therapy. The authors present the current understanding of the mechanisms underlying this observed interaction and outline areas requiring further investigation.

Simonin and colleagues developed the first next-generation sequencing (NGS)–based outcome prediction model in T-cell acute lymphoblastic leukemia (T-ALL). Targeted whole-exome sequencing of 72 T-ALL–related genes was performed on 198 adult patients and 242 pediatric patients in the GRAALL-2003/2005 and FRALLE2000T protocols, respectively. NGS-based classification improved prognostication over usual assessment of postinduction minimal residual disease and white blood cell counts and identified an adverse-risk and a favorable-risk group with a 5-year cumulative incidence of relapse of 51% and 12%, respectively.

Dei Zotti et al report on preclinical studies of immune checkpoint inhibitor (ICPi)–induced autoimmune hemolytic anemia (AIHA). The authors studied a novel mouse model that develops autoantibodies, hemolysis, and mortality in response to ICPi. They identified changes in T cells that may underlie the development of this complication, with 2 populations of regulatory T cells that are reduced by ICPi with an increase in an inflammatory helper T-cell population. They also identified a novel CD39⁺ T-cell population predictive of AIHA that is found in patients with AIHA. CD39 is an ATPase, and the authors demonstrate in the mouse model that increasing ATPase activity mitigates AIHA, suggesting a possible entry point for treating patients with ICPi-AIHA.

T-prolymphocytic leukemia (T-PLL) is a mature chemoresistant T-cell neoplasm that has a poor prognosis with transient responses to alemtuzumab and no effective salvage therapy in patients ineligible for allogeneic transplantation. von Jan and colleagues investigated therapeutic vulnerabilities in patient-derived mouse xenografts and demonstrated that combining a P53 DNA damage response inhibitor (idasanutlin) with DNA-damaging agents (cladribine) is a promising potential therapy for T-PLL.

Fluorescence in situ hybridization (FISH) is the method for identifying high-grade B-cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma [DHL]). Unbalanced MYC patterns, where a signal is lost, are usually identified as equivocal, raising the issue as to whether the gene is deleted or rearranged. Collinge and colleagues studied a cohort of 297 DHL tumors, 13% of which had unbalanced break-apart signals. MYC rearrangement was identified in 71% of these tumors with MYC gene overexpression, suggesting that these tumors should be reported as DHL.

Myelodysplastic syndromes (MDS) are clonal stem cell disorders characterized by abnormal myeloid cell differentiation and cytopenias. The vast majority of MDS have recognizable genetic changes, but current classifications are primarily defined morphologically. Bernard and a group of international contributors performed targeted sequencing of a 152-gene panel on 3233 patients with MDS to assess gene mutations, copy-number changes, and copy-neutral loss of heterozygosity. The authors characterized 16 molecular groups representing 86% of the patients, while 14% of patients lacked identifiable aberrations in driver genes. They confirm previously identified entities but also unveil novel subgroups in work that will likely influence future classification systems.

α-Thalassemia (AT) is a commonly occurring hemoglobinopathy related to deletion of α-globin genes. Severe AT reflects deletion of 3 or 4 of the α-globin genes and is associated with severe hemolytic anemia or prenatal mortality, respectively. AT has been difficult to study because of the absence of mouse models. Chappell et al have created a model of severe AT via lipid nanoparticle delivery targeting stem cells with a Cre messenger RNA, leading to deletion of α-globin genes and transplanting transduced stem cells into adult mice. Delivery of a lentiviral α-globin gene ameliorates the disease. These studies provide an important model of AT, while the efficacy of nanoparticle transduction offers hope for in vivo transduction.