Blood Cancer Discovery最新文献

The standard of care for multiple myeloma has rapidly evolved to include immune-based therapies. However, achieving durable immune control and long-term survival, particularly in high-risk patients, remains difficult. In this article, we review the immune effects of existing and emerging therapies, dissect key drivers of resistance, highlight rational combinations and treatment-sequencing strategies, and summarize ongoing clinical trials that aim to optimize durable immune control. We discuss how the application of these biological and clinical insights may help us rethink multiple myeloma treatment to fully eradicate residual disease and elicit sustained natural and/or synthetic tumor-specific immunity.

Significance: Preclinical and clinical insights are reshaping how immune-based therapies are used in multiple myeloma. This review explores how optimizing the integration of natural and synthetic immunity can support a shift from disease control to deep, durable immune eradication, paving the way for personalized immune strategies tailored to individual immune profiles.

Cancer cells display extensive heterogeneity that influences therapy response and clinical outcome, yet the underlying mechanisms remain incompletely understood. Recent studies reveal that the developmental state and molecular plasticity of target cells, together with genetic lesions, drive cellular transformation, disease heterogeneity, and treatment response in hematologic malignancies. See related article by Hartmann et al., p. 306 (9) See related article by Wang et al. (8).

In this commentary, we open the debate on what can be expected from artificial intelligence (AI) in the diagnosis of hematologic cancers. We discuss the key factors that make AI solutions robust, trustworthy, and, above all, generalizable, with particular emphasis on the importance of dataset quality in shaping the performance and effectiveness of AI models.

Mitochondria regulate critical cellular processes beyond energy production, including organelle quality control, programmed cell death, and intercellular and interorganellar communication. In hematologic malignancies, mitochondria undergo adaptations through mechanisms including genetic mutations, metabolic reprogramming, mitochondrial transfer, fusion, and mitophagy. These alterations create heterogeneity, contribute to therapeutic resistance, and can also reshape the tumor microenvironment to promote progression. Collectively, these findings suggest that mitochondria represent a promising frontier in next-generation therapeutics, with emerging strategies such as mitochondrial-targeted small molecules and mitochondrial transplantation holding significant therapeutic potential.

Significance: In this review, we summarize the functions of mitochondria beyond energy production and highlight the heterogeneity of mitochondrial functional adaptations in hematologic malignancies, as well as the vital role of mitochondrial alterations in reshaping the tumor microenvironment. Understanding these changes is critical to deciphering the pathophysiology of hematologic malignancies.

CD70 is highly expressed in many cancers, including multiple myeloma. We show in two cohorts of patients with multiple myeloma 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 IHC. Moreover, we demonstrate the feasibility of targeting CD70 in myeloma using NK cells engineered with a chimeric antigen receptor (CAR) incorporating the CD70 cognate receptor CD27 and IL-15 (CAR27/IL-15). CAR27/IL-15 NK cells exerted potent in vitro and in vivo cytotoxicity against CD70+ multiple myeloma cells, comparable with 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 multiple myeloma, 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).

Significance: We demonstrate that CD70 expression is elevated in patients with high-risk multiple myeloma and in patients with t(4;14) translocation. CD70-targeting CAR NK cells exhibit potent cytotoxicity against CD70+ multiple myeloma cells and significantly improve survival in xenograft mouse models of multiple myeloma, even in the absence of BCMA expression. See related commentary by Benson Jr and Caligiuri, p. 166.

Persistent fetal gene expression in childhood neoplasms is usually explained by a maturation block originating in the prenatal phase. In contrast, reactivation of fetal genes in adult malignancies is considered a consequence of oncofetal reprogramming (OFR) and is associated with aggressive disease. By reconstructing epigenetic ontogeny in juvenile myelomonocytic leukemia (JMML), we identified a postnatal maturation state of JMML stem cells with high transcriptional plasticity indicative of OFR in high-risk disease. Similarly, postnatal activation of oncogenic signaling by inducible Ptpn11E76K mutation in mice triggered molecular plasticity and reactivation of fetal gene expression. Integrative multi-omics analysis revealed aberrant CD52 expression as a feature of high-risk JMML stem cells. Anti-CD52 treatment depleted JMML stem cells and blocked disease propagation in xenograft models. Our results challenge the prevailing maturation block model of pediatric leukemogenesis and establish RAS-associated stem cell plasticity as a determinant of OFR and potential therapeutic vulnerabilities in high-risk JMML.

Significance: Persistent fetal gene expression in pediatric malignancies is considered a consequence of prenatal maturation blockade. In this study, we demonstrate that oncogenic PTPN11 mutations enhance cellular plasticity. This leads to partial restoration of fetal molecular programs, creating new therapeutically exploitable vulnerabilities. See related commentary by Miao and Xu, pp. 168.

Multiple myeloma is a malignancy of clonally expanded plasma cells shaped by complex interactions with the immune microenvironment (IME). To investigate immune correlates of treatment response and disease progression, we conducted multi-omics profiling including CD138neg single-cell RNA sequencing of 243 bone marrow samples from 102 patients (631,226 cells) and CD138pos bulk RNA and whole-genome sequencing from 209 samples. In longitudinal analyses, interferon-γ signaling associated with markers of impaired T-cell memory after autologous stem cell transplant, whereas naïve B-cell abundance and immunoglobulin diversity correlated with improved progression-free survival (HR = 0.48; P = 2.3e-4). At disease progression, multiple myeloma cells upregulated cancer-testis antigens (CTAg) and immune effector genes, with concurrent B-cell depletion, enrichment of myeloid-derived suppressor cell expression, and phenotypic T-cell exhaustion. These findings highlight dynamic immune-tumor interactions, identifying naïve B-cell reconstitution as a biomarker of durable response and CTAgs as potential targets for high-risk disease at progression.

Significance: Longitudinal profiling of multiple myeloma and the IME revealed dynamic immune-tumor interactions across the disease course. Altered expression in CD8+ T cells limited memory phenotype after transplant, whereas naïve B-cell recovery associated with sustained treatment response. At progression, CTAg expression associated with immunosuppression, revealing novel mechanisms of immune dysregulation.

The B-cell receptor (BCR) is central to normal and malignant B-cell biology, integrating intrinsic programs with microenvironmental cues to shape cell fate. Across mature B-cell lymphomas, differences in BCR expression, class, and signaling mode define distinct pathogenetic routes and therapeutic vulnerabilities, ranging from BCR-dependent to BCR-silent states. We propose a BCR blueprint that positions these tumors along a continuum of signaling modes and class-imposed functions, emphasizing germinal center-derived lymphomas. This framework links specific BCR states to genetic lesions and microenvironmental niches, underscoring the value of routinely monitoring BCR features to track tumor evolution and inform therapy.

Significance: B-cell lymphomas exploit diverse BCR expression levels, classes, and signaling modes that span BCR-addicted to BCR-silent states and shape their genetic programs and therapeutic dependencies. A unified BCR blueprint reframes these diseases along a continuum of BCR signaling and isotype-driven biology, particularly in germinal center-derived entities. Embedding this blueprint into routine clinical testing has the potential to improve prediction of response or resistance to BCR-targeted and other mechanism-based therapies.

Multiple myeloma (MM) is a plasma cell (PC) cancer that depends on the bone marrow (BM) microenvironment for disease establishment and progression. Here, we spatially mapped BM biopsies from patients with MM, smoldering MM, and monoclonal gammopathy of undetermined significance by imaging mass cytometry. We found that PCs near bone surfaces displayed markers of quiescence and demonstrated a distance-to-bone-dependent expression of IL-32 in patients with bone disease, consistent with their role in promoting bone loss in MM. We identified two distinct PC neighborhoods termed PC_OXPHOS, characterized by focal PC growth, enrichment of endothelial cells, and oxidative phosphorylation; and PC_MYELOID, characterized by PCs interspersed with immune cells, featuring a glycolytic phenotype. Notably, imaging-inferred interactions between PCs and CD4+ T cells was an independent negative predictor for progression-free survival. Our work underscores spatial context as a key factor in understanding MM pathogenesis and the potential for spatial analyses to improve MM risk stratification.