Blood Cancer Discovery最新文献

UBTF tandem duplications (UBTF-TD) define a high-risk molecular subtype of acute myeloid leukemia (AML). Although menin inhibitors show therapeutic promise in UBTF-TD AMLs, acquired resistance remains a challenge. In this study, we used proteomic, epigenetic, and functional analyses to uncover mechanisms underlying UBTF-TD leukemogenesis. Biochemical studies showed that UBTF-TDs result in structural destabilization and create nuclear export signal (NES) motifs, which mediate direct interactions with exportin-1 (XPO1). In cord blood CD34+ UBTF-TD models, these interactions were shown to drive aberrant chromatin binding and transcriptional activation of genes dysregulated in UBTF-TD tumors. Through mutagenesis, we demonstrated that these NES motifs are critical for localization of UBTF-TD proteins to chromatin, transcriptional dysregulation, and cellular proliferation and differentiation. In preclinical UBTF-TD models of human leukemia, we found that XPO1 inhibition disrupts UBTF-TD chromatin localization, reduces tumor burden, and promotes differentiation. These mechanistic findings highlight XPO1 inhibition as a potential therapy for UBTF-TD AMLs.

Significance: UBTF tandem duplications are a high-risk AML subtype. We identified a mechanism in which UBTF-TDs result in the generation of NES motifs, enabling aberrant interaction with XPO1. We found that XPO1 inhibitors block this interaction and impair leukemia growth, identifying a possible therapeutic strategy in UBTF-TD AML. See related commentary by Adams, p. 15.

Intratumoral heterogeneity can affect the competitive fitness and chemoresistance of individual cancer cells. In acute myeloid leukemia (AML), both genetic and functional heterogeneity contribute to chemoresistance, resulting in relapse. Whereas the role of cell-extrinsic factors has been described for AML relapse, whether interactions between cancer cells affect chemoresistance is not fully known. In this study, we demonstrated that a dominant leukemic fraction can suppress the proliferation and expansion of other leukemic cells and that this suppression is reversible. This suppression is mediated in part by both type I and type II intra-leukemic interferon signaling and dependent on BST2. Importantly, blocking antibodies to type II interferon receptor activated the cycling of this suppressed cell fraction and sensitized the cells to subsequent chemotherapy treatment. Our findings suggest that interactions between functionally heterogeneous leukemic fractions can affect competitive fitness and treatment response, highlighting interferon signaling as a potential therapeutic target to counter chemoresistance.

Significance: AML presents a significant challenge in clinical management due to its poor prognosis and high rates of relapse following chemotherapy. Using multiple models of primary human AML, we demonstrate that competitive interactions between leukemia cells affect clonal dynamics and therapy resistance, thereby identifying a potential strategy to improve patient outcomes. See related commentary by Papaioannou and Aifantis, p. 18.

Despite recent advances, multiple myeloma remains essentially incurable for most patients, particularly those with high-risk cytogenetics and those whose disease relapses after BCMA-targeting therapies. A novel CD27 CAR_sIL15 NK cell targeting CD70 may offer new hope in this area of urgent, unmet medical need. See related article by Lin et al., p. XX .

CAR-T cells targeting CD22 (CAR22) are associated with IEC-HS. However, CAR22-related IEC-HS has not been detailed in LBCL or adults with B-ALL. Here, we describe the manifestations of IEC-HS in patients with LBCL and B-ALL. IEC-HS was common, occurring in 19 out of 54 patients (35%); 8 patients required treatment and 11 patients did not. Development of IEC-HS was associated with a higher non-relapse mortality risk yet lower relapse. CAR expansion in peripheral blood significantly associated with IEC-HS severity. Cytokine profiling identified 41 cytokines primarily related to the IFNg, TNFa and IL1 families that correlated strongly with IEC-HS severity. We developed a parsimonious model composed of IFNg, IL10 and IL1RA that accurately predicted grade 2+ IEC-HS on D+14 better than the full signature (AUC 0.93 vs 0.75, p = 0.038). In summary, we found IEC-HS predicts higher NRM and lower relapse after CAR22 and that cytokine signatures predict severe IEC-HS.

Multiple myeloma (MM) is a malignancy of clonally expanded plasma cells shaped by complex interactions with the immune microenvironment. 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, while naïve B cell abundance and immunoglobulin diversity correlated with improved progression-free survival (HR = 0.48, p = 2.3e-4). At disease progression, MM cells upregulated cancer-testis antigens 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 cancer-testis antigens as potential targets for high-risk disease at progression.

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, post-natal 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.

Clonal hematopoiesis (CH) increases with age and is associated with severe outcome in the course of infections or tumor development. Understanding the environmental conditions that favor mutant clones and the CH-immune system response to such environments is key to designing therapeutic strategies to stall the expansion of mutant clones and the development of CH-associated pathologies. Using human cells, we unravel a cell-specific and opposite impact of TET2 mutations on hematopoietic stem and progenitor cells (HSPC) compared to their myeloid progeny. Multi-omic analyses reveal that TET2-mutant HSPCs exhibit intrinsic epigenetic silencing of AP-1 transcription factors and a blunted transcriptional adaptation to systemic inflammation. Conversely, monocyte-macrophage trajectory derived from TET2Mut HSCs contributes to exacerbated inflammation. Together, these findings reconcile how TET2-mutant CH can simultaneously promote increased stemness within the HSPC compartment and heightened inflammation through its myeloid progeny, providing mechanistic insight into how TET2-CH expands under inflammatory stress.

Extramedullary multiple myeloma (EMM) is a high-risk feature of multiple myeloma (MM) associated with increased resistance to treatments, including modern immunotherapies, and shorter survival. Composition and functional state of immune cells within the EMM tumor microenvironment (TME) remain poorly understood. Using single-cell RNA sequencing, flow cytometry, and spatial transcriptomics, we revealed significant differences in the EMM TME compared to MM bone marrow. T and NK cells were verified as the most abundant immune subsets in the EMM TME. Compared to the bone marrow counterparts, we found these tumors to have a significantly reduced effector-to-tumor cell ratio, significantly lower number of CD4⁺ T cells, and increased proportion of regulatory CD16⁻ NK cells. We observed a high proportion of exhausted, tumor-reactive CD8+ T cells in roughly half of EMM tumors. Furthermore, we identified elevated expression of immune checkpoints, such as PD-1 on CD8⁺ T cells and KLRC1 (NKG2A) on CD16⁻ NK cells.

Genomic antigen loss is a recurring mechanism of resistance to chimeric antigen receptor T-cell (CAR-T) and T-cell engagers (TCE) in relapsed/refractory multiple myeloma (RRMM). Yet, it remains unclear whether these events are acquired under treatment or merely selected from preexisting, undetectable clones. By leveraging chemotherapy mutational signatures as temporal barcodes within whole-genome sequencing data, we could time genomic antigen escape in 4 of 11 patients with RRMM. In all cases, the biallelic loss was driven by genomic events acquired after exposure to BCMA- and GPCR5D-targeted CAR-T/TCE and not present at baseline. Longitudinal digital PCR analysis corroborated that resistance mutations were undetectable at therapy initiation but emerged preceding relapse. Among 752 newly diagnosed patients, only 2.7% and 9% had monoallelic inactivation of TNFRSF17 and GPCR5D, respectively, with no biallelic loss. Our findings suggest limited utility of mutational screening prior to CAR-T/TCE while underscoring the importance of dynamic surveillance during therapy.

Significance: Multiple myeloma has been demonstrated to recurrently develop resistance to T-cell redirection via genomic antigen escape. By leveraging chemotherapy mutational signatures, we demonstrate that somatic antigen-escape mechanisms are uniformly acquired following treatment initiation and not selected from among preexisting clones, emphasizing the importance of dynamic longitudinal surveillance for their emergence. See related commentary by Kauer et al., p. 532.

The real-world effectiveness of the bispecific antibody teclistamab seems to be lower than the efficacy observed in pivotal registration trials. Understanding the drivers of this effectiveness-efficacy gap is essential for guiding the rational selection of patients most likely to benefit, optimizing bispecific antibody therapy in high-risk populations and ultimately advancing more personalized treatment strategies while supporting sustainable models of care. See related article by Razzo et al., p. 561.