In This Issue

Abstract

Inflammatory toxicities resulting from CAR T-cell therapy are common, but clinical features contributing to risk of these toxicities are not well understood. Saini et al. profiled peripheral blood cells of B-cell lymphoma patients prior to CD19-targeting CAR T-cell treatment and found that patients with clonal hematopoiesis (CH) were more likely to experience severe toxicities and therapy-related myeloid neoplasms compared to patients without CH. CH driven by mutations in DNMT3A, TET2, or ASXL1 conferred an especially greater risk of toxicity. This study highlights a high-risk segment of the CAR T recipient patient population and adds to the body of work associating CH with various inflammatory conditions.See article, p. 385.Relapse of acute myeloid leukemia (AML) after allogeneic bone marrow transplantation has been linked to immune evasion due to reduced expression of major histocompatibility complex class II (MHCII) proteins. Here, Eagle et al. developed a transcription network decomposition algorithm that identified a tetrad of transcription factors (TF) responsible for reduced expression of MHCII at relapse. Blasts with altered TF abundance and silenced MHCII expression were detectable at the time of the initial leukemia diagnosis. The results point to an adaptive transcriptional mechanism of immune escape through combinatorial TF fluctuations resulting in emergence of cells with a silenced T-cell stimulation program.See article, p. 394.Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia with prominent erythroid differentiation and a poorly understood molecular basis. Takeda et al. performed a comprehensive genetic study of 124 AEL cases and revealed that a subset showing extreme (>80%) erythroid differentiation is characterized by multi-hit TP53 alterations, gains/amplifications of EPOR/JAK2, and is associated with a very poor prognosis. Cells from these AEL cases exhibited elevated STAT5 phosphorylation with enhanced proliferation and heme metabolism, and frequently showed sensitivity to ruxolitinib treatment in vitro and in xenograft models, suggesting a potential role of JAK2 inhibition in AEL therapeutics.See article, p. 410.Han and Deng et al. show that mutation-associated low expression of MHC class II (MHCII) on follicular lymphoma (FL) tumor B cells is linked to significant differences in the abundance and gene expression patterns of tumor microenvironment T-cell subsets, including cytotoxic CD4+ T cells. Inferred relative abundance of T-cell subsets in FL defined major microenvironment subtypes, including a “cold” subtype with inferior outcome. Low tumor B-cell MHCII expression was also associated with a reduction in immunotherapeutic target expression. This study provides a framework to consider FL microenvironment characteristics and subtypes in the design and assessment of immune- and cellular-therapy studies.See article, p. 428.Inactivating mutations in TET2 are common in acute myeloid leukemia (AML) and in preneoplastic blood progenitors, suggesting TET2 function is an early barrier to leukemogenesis. To understand which of the TET2-dependent gene circuits are relevant to leukemogenesis, Aivalioti et al. interrogated Tet2 contributions to myeloid differentiation orchestrated by transcriptional master regulator PU.1. Decreased PU.1 activity is commonly observed in AML. Mice with decreased dosages of PU.1 and Tet2 maintain healthy blood formation but develop AML with age. Similar to human AML, progenitor cells from the leukemic mice fail to activate myeloid lineage genes. Hypermethylation at PU.1 binding sites in the enhancer regions of these genes in leukemia points to functional cooperation between PU.1 and Tet2 in sustained activation of myeloid gene program as a critical barrier to leukemogenesis.See article, p. 444.