Blood Cancer Discovery最新文献

CD70 is highly expressed in many cancers, including multiple myeloma (MM). We show in two cohorts of patients with MM that CD70 is elevated in several high-risk disease categories and correlates with poor survival. These findings were validated using single-cell RNA sequencing, flow cytometry and immunohistochemistry. Moreover, we demonstrate the feasibility of targeting CD70 in myeloma using natural killer (NK) cells engineered with a chimeric antigen receptor (CAR) incorporating the CD70 cognate receptor CD27 and IL-15. CAR27/IL-15 NK cells exerted potent in vitro and in vivo cytotoxicity against CD70+ MM cells, comparable to CAR27/IL-15 T cells, and remained effective in BCMA-knockout models. Collectively, these results establish CD70 as a promising therapeutic target for high-risk MM, particularly for patients who relapse after BCMA-directed therapy, providing preclinical support for the ongoing phase I/II clinical trial of CD70-targeting CAR-NK cells (NCT05092451).

In this issue of Blood Cancer Discovery, Newman and colleagues investigated the impact of genetic ancestry on molecular subtypes, genomic alterations, and survival outcomes in a diverse cohort of patients with T-cell acute lymphoblastic leukemia. They demonstrated that the prognostic utility of genomic alterations varied by ancestry, in particular, with NOTCH1 mutations having no prognostic utility in patients of predominantly African ancestry, and their findings highlight the importance of considering genetic ancestry in the risk stratification of patients with T-ALL. See related article by Newman et al., p. 412.

In a large retrospective multicenter study of patients with acute myeloid leukemia treated with hypomethylating agents and venetoclax, Lachowiez and colleagues examine the interplay among genetic mutations, disease phenotype, and clinical outcomes. They show that within genetic subgroups-particularly NPM1 wild-type cases-monocytic differentiation is linked to poor treatment response and inferior long-term prognosis, adding a phenotypic layer to genetics-based response prediction. See related article by Lachowiez et al., p. 437.

The World Health Organization fifth edition and International Consensus Classification for myeloid neoplasms both incorporate empirical numerical thresholds to morphologic and molecular features defining certain disease entities. However, the clinical implications of these thresholds remain unclear. We analyzed a large cohort (N = 6,976) of patients with myeloid neoplasms to evaluate the impact of proposed yet different numerical thresholds for variant allele frequency of genetic mutations or hematologic parameters set forth by the World Health Organization fifth edition and International Consensus Classification for classification of SF3B1-mutated myelodysplastic neoplasms, NPM1-mutated acute myeloid leukemia (AML), and oligomonocytic chronic myelomonocytic leukemia. Our analysis demonstrated that the clonal burden of SF3B1 mutation in myelodysplastic neoplasms informs classification and prognosis. Our findings support the notion that NPM1 mutation should be AML-defining regardless of blast percentage and highlight the adverse prognostic impact of the cumulative number of myelodysplasia-related mutations in NPM1-mutated AML. Finally, we provide evidence that integrating specific molecular signatures could improve the accuracy of oligomonocytic chronic myelomonocytic leukemia classification.

Significance: Using comprehensive clinical and molecular profiling, this study provides a data-driven approach for evaluating numerical thresholds of variant allele frequency or hematologic parameters (i.e., blast percentage and absolute monocyte count) included in current classification schemas across a spectrum of myeloid malignancies, enabling refinement of disease classification and prognostication.

Resistance to venetoclax (VEN)-based therapy in acute myeloid leukemia (AML) includes genetic (i.e., mutations in N/KRAS, FLT3-ITD, TP53) and phenotypic (i.e., monocytic differentiation) features. Whether monocytic differentiation contributes to clinical VEN resistance secondary to a genetic bias remains unknown. This multimodal, multicenter, international analysis, inclusive of 678 patients, comprehensively characterized the prognostic role of monocytic differentiation in patients with AML treated with hypomethylating agents combined with VEN. AML genetics and monocytic differentiation (HR = 1.89; 95% confidence interval, 1.35-2.66; P < 0.001) in NPM1 wild-type cases correlated with an increased risk of death, clustering of centralized quantitative multiparameter flow cytometry data, evaluation of RNA sequencing-derived AML maturation stage, and single-cell proteogenomics linked driver mutations with AML phenotype and antiapoptotic gene expression. This comprehensive analysis of AML genetics, phenotype, and antiapoptotic protein expression highlights the complementary role these factors impart following VEN-based therapy.

Significance: AML with monocytic differentiation often occurs in the context of co-occurring mutations within signaling pathways. In certain AML subgroups (such as NPM1 wild-type and signaling pathway gene-mutated), a monocytic phenotype is associated with decreased overall survival following VEN-based therapy. See related commentary by Renders, p. 403.

Ionizing radiotherapy (RT) is a widely used treatment strategy for malignancies. In solid tumors, RT-induced double-strand breaks lead to the accumulation of insertion-deletions (indels; ID), and their repair by nonhomologous end joining has been linked to the ID8 mutational signature in surviving cells. However, the extent of RT-induced mutagenesis in hematologic malignancies and its impact on their mutational profiles and interplay with commonly used chemotherapies has not yet been explored. In this study, we interrogated 580 whole-genome sequence (WGS) samples from patients with large B-cell lymphoma, multiple myeloma, and myeloid neoplasms and identified ID8 only in relapsed disease. Yet ID8 was detected after exposure to both RT and mutagenic chemotherapy (i.e., platinum and melphalan). Using WGS of single-cell colonies derived from treated lymphoma cells, we revealed a dose-response relationship between RT and platinum and ID8. Finally, using ID8 as a genomic barcode, we demonstrate that a single RT-surviving cell may seed distant relapse.

Significance: RT and the ID8 indel signature are related, but their genomic impact on hematologic malignancies is unclear. Leveraging WGS, we linked ID8 to both RT and mutagenic chemotherapy and validated that platinum can induce ID8. We used ID8 as a genomic barcode to reveal that RT-resistant cells may seed systemic relapse.

Aberrant levels or structures of RNA isoforms are a hallmark of many cancers, including acute myeloid leukemia (AML), yet their role in AML chemoresistance remains unclear. We conducted a paired analysis of RNA isoform changes in patients with AML before therapy and at relapse after chemotherapy and identified intragenic DNA methylation at the proximal promoter of the transcription factor RUNX1, which resulted in elevated expression of the long-isoform RUNX1C through its alternative distal promoter. The unique N-terminal region of RUNX1C orchestrated an isoform-specific transcriptional program that promoted chemoresistance, with its direct target BTG2 playing a role in chemotherapy resistance. BTG2 promoted rRNA deadenylation, resulting in decreased mRNA expression and stability. Deletion of rRNAs increased cellular quiescence. Moreover, RNA-based targeting of RUNX1C reactivated quiescent leukemia cells and enhanced chemotherapy efficacy. These findings delineated an isoform-specific transcriptional circuit that governed chemotherapy response, providing a potential therapeutic strategy to mitigate AML recurrence.

Significance: This study identifies RUNX1C as a contributor to AML chemoresistance and an inducer of quiescence through BTG2. Targeting RUNX1C with RNA-based approaches disrupts this state and improves chemotherapy response, highlighting RUNX1C inhibition as a promising strategy to overcome resistance and enhance treatment efficacy in AML.

Myeloid cells are central players in innate immunity and inflammation. Their function is regulated by the adapter protein TRAF3. We previously reported that aging myeloid cell-specific TRAF3-deficient (M-Traf3-/-) mice spontaneously develop chronic inflammation and B-cell lymphoma (BCL). In this study, we aimed to identify the internal trigger of this disease phenotype in these mice. We first detected gut microbiota dysbiosis and transmigration of commensal bacteria (CB) to the liver in aging M-Traf3-/- mice. Interestingly, depletion of CB using antibiotics effectively prevented BCL development in these mice. Systemic IgG responses against CB were induced and the IgH CDR3 sequences of malignant B-cell clones of M-Traf3-/- mice showed high homology to prevalent bacteria-reactive Ig clonotypes. Furthermore, M-Traf3-/- mice with BCL exhibited high serum titers of antibodies against CB. Together, our findings offer insights into the mechanisms underlying increased risks of B-cell lymphomagenesis observed in patients with compromised innate immunity.

Significance: We present evidence that microbiota dysbiosis in animals with compromised innate immunity increases risk of intestinal bacteria transmigration to internal organs, which subsequently induces malignant transformation of CB-reactive B-cell clones. Accordingly, antibiotic treatment or blocking CB transmigration may serve as a strategy for preventing BCL in patients with innate immunodeficiency.

There is growing interest from both patients and clinicians in understanding the role nutrition plays across hematologic malignancies. In this study, we highlight key unanswered questions related to studying dietary interventions in hematologic malignancies, including questions about how to conduct research, trial design considerations, and integrating dietary interventions into hematologic cancer care and policy.

Multiple myeloma remains incurable despite advances in immunotherapies like chimeric antigen receptor (CAR) T-cell therapy. This study investigates the role of metabolites and gut microbiota in clinical outcomes in patients treated with the humanized B-cell maturation antigen (BCMA)-directed CAR-T therapy ARI0002h. Stool metabolites, particularly succinate, were associated with CAR T-cell phenotypes and persistence in patients. In CAR T-cell culture, succinate supplementation enhanced CD4+ central memory phenotype and respiratory capacity. In a murine myeloma model, a succinate-enhancing diet significantly improved CAR T-cell persistence and showed a trend toward better tumor control. Furthermore, Acidaminococcaceae, Monoglobaceae, or Akkermansiaceae, along with specific metabolites, were associated with CAR T-cell clinical outcomes. These multimodal profiles were integrated into response models, including one that identified patients likely to achieve a complete response by days 100 and 180 after infusion. These findings suggest that metabolites and gut microbiota correlate with CAR T-cell therapy responses and can be a valuable tool for risk assessment.

Significance: This study integrates microbial profiles into response models, providing a tool to identify patients with multiple myeloma who may benefit from BCMA-directed CAR T-cell therapy optimization by identifying bacterial taxa and metabolites associated with CAR T-cell persistence and therapeutic outcomes.