Highlighted Research Articles

CAR T-cell therapies produce durable responses for some patients with large B-cell lymphoma, but outcomes are poor with high tumor burden or limited CAR T-cell expansion. Here Pomeroy and colleagues apply a population-pharmacokinetic/pharmacodynamic model of axicabtagene ciloleucel to explain how a high tumor-to-CAR T-cell ratio is effectively a resistance mechanism, with lymphoma proliferation outpacing cytotoxicity. Simulations predict that pre-infusion tumor debulking can shift this ratio to favor CAR T cells and improve the rate of durable response. These results complement clinical evidence on the benefits of bridging therapy and motivate research on debulking strategies to enhance CAR T-cell efficacy.See article, p. 41.UBTF tandem duplications (UBTF-TDs) define a high-risk subtype of myeloid malignancy, yet molecular insights into disease pathogenesis are limited. Barajas and colleagues showed that UBTF-TDs generate nuclear export signal motifs that enable aberrant binding to the exportin, XPO1, leading to mislocalization of UBTF-TD on chromatin and activation of transcriptional programs associated with self-renewal. Disruption of these motifs, or pharmacologic inhibition of XPO1, blocked chromatin engagement, promoted cellular differentiation, and reduced disease burden in preclinical models. This reveals an XPO1-dependent mechanism of leukemic growth and a potential therapeutic vulnerability in UBTF-TD driven myeloid neoplasms.See article, p. 51.Acute myeloid leukemia (AML) is marked by intra-tumoral heterogeneity that contributes to relapse and chemoresistance. In this study, Karigane and colleagues used models with primary human AML samples to demonstrate that dominant leukemic cells suppress other leukemic populations through interferon (IFN) signaling and BST2, thereby creating a reversible dormant state in a subset of leukemic cells. Blocking antibodies to the type II IFN receptor reactivated these suppressed cells, making them more susceptible to chemotherapy. These findings highlight an intra-leukemic interaction that shapes leukemic cell fitness and chemoresistance, and suggest that targeting IFN signaling may offer a therapeutic strategy to overcome chemoresistance in AML.See article, p. 68.Resistance to BTK inhibitor (BTKi-R) therapy in chronic lymphocytic leukemia (CLL) often arises through mutations in the BTK gene. In this study, Gordon and colleagues performed single-cell RNA sequencing of CLL samples resistant to both ibrutinib and venetoclax, revealing robust PKCβ expression in resistant cells. Pharmacologic inhibition of PKCβ with MS-553 suppressed B-cell receptor and Wnt/β-catenin signaling in both treatment-naïve and BTKi-R CLL. PKCβ inhibition increased CLL cell dependence on BCL-2, and combined treatment with MS-553 and venetoclax produced synergistic cytotoxicity against primary CLL cells and extended survival in a mouse model of CLL. These findings establish PKCβ as a potential therapeutic target for BTKi-resistant CLL.See article, p. 85.Mo and colleagues describe preclinical results for golcadomide, a cereblon-modulating (CELMoD) agent developed for diffuse large B-cell lymphoma (DLBCL). Golcadomide demonstrated rapid and deep degradation of transcription factors IKZF1 and IKZF3, driving strong antiproliferative and apoptotic activity and outperforming the immunomodulatory agent lenalidomide in preclinical models. It upregulated interferon-inducible genes, downregulated MYC, and preferentially accumulated in lymphoma tissues in mouse xenografts, leading to significant tumor regression and durable, tumor-free survival. Genome-wide CRISPR screens identified modulators of golcadomide response, supporting its dual tumor-killing and immunomodulatory mechanisms. These findings provide rationale for golcadomide as a therapeutic candidate for clinical development in DLBCL.See article, p. 104.Altered transcriptional networks in multiple myeloma (MM) cells create non-oncogene dependencies on specific transcription factors (TFs). Fulciniti and colleagues identified a tumor suppressor role for ID2 in MM, via its ability to bind to and inhibit the activity of the TF TCF3. ID2 downregulation observed in MM cells promoted proliferation by enhancing TCF3 activity, thereby creating a reliance on this TF. Soluble factors secreted by bone marrow stromal cells further suppressed ID2 while boosting TCF3 activity. Therefore, this study suggests that targeting the interplay between ID2 and TCF3 could offer a potential therapeutic strategy to inhibit MM growth and counteract microenvironmental influences.See article, p. 129.This comparative analysis examines two strategies for relapsed/refractory DLBCL: anti-CD19 + anti-CD22 CAR T-cell therapy alone or combined with autologous stem cell transplantation (ASCT) by propensity score–matched analysis of two single-arm trials based on the same CAR T-cell product. The combination therapy achieved higher response rates and significantly improved survival, with manageable long-term safety. Independent predictors of better outcomes included early complete response and receipt of combined therapy. These findings suggest that integrating CAR T-cell therapy with ASCT may optimize efficacy and safety, offering a promising strategy for high-risk patients.See article, p. 142.