The PIM family of serine/threonine kinases (PIM1, PIM2, and PIM3) are involved in the development of cancer and represent promising therapeutic targets. We investigated the therapeutic potential of targeting PIM kinases in diffuse large B-cell lymphoma (DLBCL), particularly the activated B-cell-like (ABC) subtype, using the pan-PIM inhibitor AZD1208. We demonstrated that PIM1 and PIM2 are more highly expressed in ABC- cells than in germinal center B-cell-like (GCB) -DLBCL cells, and that ABC-DLBCL cell lines are more sensitive to PIM inhibition with AZD1208.
View Article and Find Full Text PDFThe role of the bone marrow (BM) microenvironment in regulating the antitumor immune response in Waldenstrom macroglobulinemia (WM) remains poorly understood. Here we transcriptionally and phenotypically profiled non-malignant (CD19 CD138) BM cells from WM patients with a focus on myeloid derived suppressive cells (MDSCs) to provide a deeper understanding of their role in WM. We found that HLA-DRCD11bCD33 MDSCs were significantly increased in WM patients as compared to normal controls, with an expansion of predominantly polymorphonuclear (PMN)-MDSCs.
View Article and Find Full Text PDFHematology Am Soc Hematol Educ Program
December 2024
Follicular lymphoma is the most common indolent lymphoma, with a favorable prognosis and survival measured in decades. However, approximately 15% to 20% of patients encounter early disease progression, termed POD24, within 24 months from diagnosis or treatment initiation. Recognizing the correlation between POD24 and a heightened risk of lymphoma-related death has sparked intensive investigations into the clinical and biological determinants of POD24 and the development of innovative treatment strategies targeting this group.
View Article and Find Full Text PDFRecent breakthroughs in research have sparked a paradigm shift in our understanding of cancer biology, uncovering the critical role of the crosstalk between tumor cells and the immune cells of the tumor microenvironment (TME) in malignant transformation. Fibroblasts have long been viewed as ancillary participants in cancer progression, often eclipsed by the prominence given to malignant cells. Novel investigations, however, have increasingly acknowledged the essential part played by the fibroblasts and their phenotypic doppelganger cancer-associated fibroblasts (CAFs) in fostering immunosuppression and promoting tumor progression.
View Article and Find Full Text PDFThe genetic era has opened the opportunity of using personalized therapeutic approaches, in part based on targeting genes with somatic mutations. For example, lymphomas harboring the highly recurrent CREBBP mutation show dependency on HDAC3, thus selective inhibition of HDAC3 reversed the epigenetic effects of CREBBP mutation, halted lymphoma growth, and induced MHC class II expression, enabling the T-cells to recognize and kill lymphoma cells. However, CREBBP wild type (WT) cells are less sensitive to this approach.
View Article and Find Full Text PDFCurrently, the role of DNA methylation in the immunoglobulin M (IgM) monoclonal gammopathy disease spectrum remains poorly understood. In the present study, a multiomics prospective analysis was conducted integrating DNA methylation, RNA sequencing (RNA-seq), and whole-exome sequencing data in 34 subjects (23 with Waldenström macroglobulinemia [WM], 6 with IgM monoclonal gammopathy of undetermined significance [MGUS], and 5 normal controls). Analysis was focused on defining differences between IgM gammopathies (WM/IgM-MGUS) compared with controls, and specifically between WM and IgM-MGUS.
View Article and Find Full Text PDFFollicular lymphoma (FL) is an indolent non-Hodgkin lymphoma of germinal center origin, which presents with significant biologic and clinical heterogeneity. Using RNA-seq on B cells sorted from 87 FL biopsies, combined with machine-learning approaches, we identify 3 transcriptional states that divide the biological ontology of FL B cells into inflamed, proliferative, and chromatin-modifying states, with relationship to prior GC B cell phenotypes. When integrated with whole-exome sequencing and immune profiling, we find that each state was associated with a combination of mutations in chromatin modifiers, copy-number alterations to TNFAIP3, and T follicular helper cells (Tfh) cell interactions, or primarily by a microenvironment rich in activated T cells.
View Article and Find Full Text PDFT-lymphocytes are prevalent in the tumor microenvironment of follicular lymphoma (FL). However, the phenotype of T-cells may vary, and the prevalence of certain T-cell subsets may influence tumor biology and patient survival. We therefore analyzed a cohort of 82 FL patients using CyTOF to determine whether specific T-cell phenotypes were associated with distinct tumor microenvironments and patient outcome.
View Article and Find Full Text PDFRE-MIND2 (NCT04697160) compared patient outcomes from the L-MIND (NCT02399085) trial of tafasitamab+lenalidomide with those of patients treated with other therapies for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are autologous stem cell transplant ineligible. We present outcomes data for three pre-specified treatments not assessed in the primary analysis. Data were retrospectively collected from sites in North America, Europe, and the Asia Pacific region.
View Article and Find Full Text PDFWhile most patients with follicular lymphoma (FL) have excellent outcomes with frontline chemoimmunotherapy (CIT), a subset of patients will experience early progression, which is associated with poor subsequent outcomes. Novel biomarkers are needed to identify high-risk patients earlier. We hypothesized that interim positron emission tomography (PET) would predict progression-free survival (PFS) in this population.
View Article and Find Full Text PDFThe standard therapies in lymphoma have predominantly focused on targeting tumor cells with less of a focus on the tumor microenvironment (TME), which plays a critical role in favoring tumor growth and survival. Such an approach may result in increasingly refractory disease with progressively reduced responses to subsequent treatments. To overcome this hurdle, targeting the TME has emerged as a new therapeutic strategy.
View Article and Find Full Text PDFThe last two decades have brought ground-breaking advances in genetics, culminating in deep profiling of the human genome and high resolution detection of genetic variants [...
View Article and Find Full Text PDFMultiple myeloma is a plasma cell malignancy that is still largely incurable, despite considerable progress in recent years. NF-κB is a well-established therapeutic target in multiple myeloma, but none of the currently available treatment options offer direct, specific pharmacologic targeting of NF-κB transcriptional activity. Thus, we designed a novel direct NF-κB inhibitor (IT848) as a drug candidate with strong potential for clinical translation and conducted comprehensive in vitro and in vivo mechanistic studies in multiple myeloma cell lines, primary multiple myeloma cells, xenograft models, and immunocompetent mouse models of multiple myeloma.
View Article and Find Full Text PDFEpigenetic reprogramming is a hallmark of lymphomagenesis, however its role in reshaping the tumor microenvironment is still not well understood. Here we review the most common chromatin modifier mutations in B cell lymphoma and their effect on B cells as well as on T cell landscape. We will also discuss precision therapy strategies to reverse their aberrant signaling by targeting mutated proteins or counterbalance epigenetic mechanisms.
View Article and Find Full Text PDFExpert Opin Pharmacother
February 2022
Introduction: Follicular lymphoma (FL) is the second most common form of B cell lymphoma and generally presents as an indolent and relatively slow-growing tumor. However, most FLs are incurable with a shortening of subsequent responses. Therefore, novel and more effective treatments are desperately needed.
View Article and Find Full Text PDFThe molecular classification of diffuse large B cell lymphoma has paved the way for precision medicine that targets oncogenic driver pathways and actionable mutations. In this issue of Cancer Cell, Wilson et al. execute a massive genomic analysis in order to identify putative molecular signatures linked to a differential response to ibrutinib plus R-CHOP.
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