Blood Cancer Discovery最新文献

Exportin-1 (XPO1/CRM1) is a validated target in hematologic malignancies best studied for its role in mediating nuclear export. In this issue of Blood Cancer Discovery, Barajas and colleagues reveal that UBTF tandem duplications found in acute myeloid leukemia complete a nuclear export sequence that enables a novel UBTF-XPO1 interaction, particularly at chromatin loci critical for leukemogenesis, thus raising the question: Could XPO1 inhibitors find new use in the UBTF-TD acute myeloid leukemia subtype? See related article by Barajas et al., p. 51.

The state of the blood cancer field and its toll on patient mortality and morbidity, adapted from the 15th edition of the annual AACR Cancer Progress Report (https://cancerprogressreport.aacr.org/progress/), is presented to the US Congress and the public.

Clonal hematopoiesis of indeterminate potential, myelodysplastic syndromes, and acute myeloid leukemia are myeloid cell disorders that exist on a spectrum. Modifiable risk factors, including obesity, insulin resistance, physical activity, dietary patterns, smoking, and the microbiome, have been implicated in myeloid cell disorder pathogenesis. Although the connection between these modifiable risk factors and their association with myeloid disorders has been studied, as of September 2025, no clinical trials are ongoing that evaluate whether lifestyle interventions can alter myeloid disorder disease progression. This article reviews myeloid disorders and their association with inflammation and how lifestyle interventions may influence disease progression.

Significance: Myeloid disorders are associated with inflammation and metabolic disorders such as obesity and diabetes mellitus. Dietary and lifestyle modifications may directly influence the pathogenesis, development, and survival by addressing inflammatory and metabolic pathways. However, additional preclinical research and large prospective clinical trials are needed to confirm these findings. This review provides an overview on myeloid disorder pathogenesis and modifiable factors that influence it, which may guide future research to reduce the myeloid disorder burden and improve outcomes for patients with clonal hematopoiesis of indeterminate potential, myelodysplastic syndromes, and acute myeloid leukemia.

Resistance of chronic lymphocytic leukemia to BTK inhibitors poses a major clinical challenge; however, there is potential to overcome this obstacle by targeting the downstream protein kinase PKCβ using the novel inhibitor MS-553. By inhibiting PKCβ, MS-553 blocks B-cell receptor signaling and WNT/β-catenin and NF-κB functions, thereby inducing apoptosis in BTK inhibitor-resistant cells. See related article by Gordon et al., p. 85.

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.