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Blood Podcast
Diffuse large B-cell lymphoma’s long-term effects on immune profiles, plasminogen activation and prevention of venous thromboembolism, and PARP inhibitors in hematological malignancies carrying epigenetic mutations
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Welcome to the September 11, 2025 episode of Blood Podcast, your source for innovative ideas and cutting edge information. Our topics are based on articles published in Blood A Journal of the American Society of Hematology. Today we'll learn about persistent changes in immune profiles in patients who have had diffuse large B cell lymphoma or dlbcl and other cancers that plasminogen activation and plasmin activity do not appear to play a role in routine physiological prevention of venous thromboembolism or VTE, and about a novel mechanism that makes hematological malignancies carrying epigenetic mutations susceptible to PARP inhibitors. We first examine data in the Blood article entitled Large B cell lymphoma imprints Dysfunctional immune phenotype that persists years after treatment by Richard Palzel of the University Hospital of Erlingen in Erlingen, Germany and colleagues. Patients with DLBCL show disease related changes in immune cell profiles that are already apparent when they are first diagnosed. These changes include higher levels of activated T cells and immune inhibitory myeloid derived suppressor cells or MDSCs, and lower levels of naive T cells. Little is known about whether and how these immune profiles change as patients with DLBCL receive treatment, achieve remission and or develop relapsed refractory disease. A better understanding of how immune profiles might change with disease stage and over time could help to shed light on patients risk of relapse, their ongoing susceptibility to infections, autoimmune disease and secondary primary malignancies, and their ability to respond to subsequent immunotherapy or vaccinations. This information is particularly important as therapies have become more effective and patients with DLBCL are living longer. The authors of the first paper that we're discussing used fresh peripheral whole blood samples to compare immune profiles in patients with DLBCL across stages, including those who were newly diagnosed in complete remission or had relapsed refractory disease. The authors found a distinctive pattern of chronic immune activation in patients with DLBCL that was present at diagnosis, became more prominent with treatment, and persisted through complete remission or relapse. Compared with healthy controls, patients with active or remitted DLBCL had high levels of monocytic MDSCS cells whose physiologic task is to resolve inflammation across disease stages. Patients with DLBCL had reduced numbers of naive central memory and regulatory T cells. Polyclonal activated T, central memory and terminal effector memory cells, on the other hand, were increased. The immune profiles of patients in remission from DLBCL more closely resembled those of patients with active lymphoma than than they did those of healthy controls, even in patients who were in complete remission for five years or more. This long lasting immune dysregulation was accompanied by decreased T cell responses to vaccines across all stages of dlbcl, with important implications for managing risk of infectious disease. As an example, the patients had functionally blunted T cell immunity against SARS CoV2 specific peptides. The authors also investigated the immune cell profiles of patients with other cancers, including active but untreated chronic lymphocytic leukemia, active or remitted acute myeloid leukemia, and active or remitted breast cancer. Each of these cancers showed a distinct pattern of immune dysregulation that was similar across patients with active or remitted disease. These patterns differed from each other and from that seen in dlbcl. These findings suggested that each type of cancer is associated with a unique immune scar that persists long after the cancer has been successfully treated. The authors used bulk RNA sequencing of T cells and MDSCs to investigate changes in gene expression in DLBCL. The gene expression signatures of T cells from patients with DLBCL were similar across disease stages and distinct from those of healthy controls in the MDSC population. Some patients in complete remission had inflammatory gene expression signatures that more closely resembled those of healthy controls than other patients with dlbcl. This finding suggested that patients in complete remission might have chronic inflammation that differs in severity. The authors also looked at serum inflammatory markers, finding interleukin 6 beta 2 microglobulin and soluble CD14 levels were increased across DLBCL stages relative to healthy controls. Mediators of innate immunity were upregulated in patients in complete remission but not those with relapsed refractory disease. As a step towards linking the observed changes in T cell populations with the presence of lymphoma, the authors injected lymphoma cells from a mouse model of non Hodgkin lymphoma into syngeneic immunocompetent mice. After 38 days, the mice showed high levels of lymphoma cell infiltration in spleen and lymph nodes, accompanied by increases in MDSCs and changes in T cell populations similar to those seen in humans with dlbcl. Taken altogether, the findings in this paper suggested that having DLBCL leads to chronic inflammation and impaired adaptive immunity, which might be compensated for by activation of innate immunity in some circumstances. In an accompanying commentary Michael Jain of the Moffitt Cancer center in Tampa, Florida, and Jonathan Couls Lartigue of McGill University in Montreal, Canada, said that these findings suggest that while cancer therapy may eradicate the tumor, it does not eradicate persistent changes in the immune system. They noted the possibility that these immune deficits might actually precede tumor formation, suggesting that immune dysregulation might be a cause rather than a consequence of cancer development. Next up, we'll discuss findings from the Blood article entitled Plasminogen activation and plasmin activity are not required to prevent venous thrombosis thromboembolism by Yaqiu Sang of the University of North Carolina in Chapel Hill, North Carolina and colleagues. The fibrinolytic system plays a well established role in resolving the fibrin rich thrombi that that lead to venous thromboembolism or VT El. Fibrinolysis is initiated by the conversion of plasminogen to plasmin catalyzed by the enzyme tissue plasminogen activator. Exogenous tissue plasminogen activator is used therapeutically to enhance clot dissolution in patients with ischemic stroke and other clotting conditions where it is associated with a risk of excess bleeding. Conversely, the the anti fibrinolytic agent transexamic acid reduces excess bleeding and bleeding related deaths in women with postpartum hemorrhage as well as in surgical and trauma patients. These observations have led to the consideration that in addition to their role in clot dissolution, plasminogen activation and plasmin activity might be involved in regulating clot formation by routinely preventing fibrin accumulation within blood vessels. This possibility has important clinical implications because it suggests that anti fibrinolytic therapies might increase the risk of VT elus far limiting their use to patients with low clotting risk. To date, however, preclinical and clinical studies of the relationship between plasminogen activation, thrombogenesis and VTE risk have yielded conflicting results. The authors of the second paper that we're discussing and examined whether plasminogen activation plays a role in VT EL risk using multiple complementary methods, including genetic, pharmacologic and proteomic investigations. Approximately 1.6 per million people have a rare congenital deficiency in plasminogen. The authors reviewed data from a patient registry that included genetic and clinical information on 107 patients with varying degrees of type 1 plasminogen deficiency and their first degree relatives. These patients shared a set of common symptoms together with variable defects in ear, oropharyngeal, respiratory, gastrointestinal and other organ systems. However, there was no history of VT El or pulmonary embolism in this patient population. Turning to mice, the authors investigated clot formation in mice with homozygous or heterozygous loss of the gene encoding plasminogen. They found no difference in clot formation in an experimental model of venous thrombosis between homozygous, heterozygous and wild type mice, including clot size, composition and timing of formation. They also tested the effects of the antifibrinolytic agent transexamic acid in wild type mice. This agent suppressed plasmin formation both in vitro in mouse blood and and in vivo in healthy mice, just as it does in humans when thrombosis formation was induced by inferior vena cava ligation. There was no difference in clot mass or composition between mice who received transexamic acid and control mice who did not. The authors expanded their human genetic studies by examining genome wide association data from a large cohort of VT El cases and non VT El controls. They found no significant associations between variants in genes involved in the plasminogen activation pathway and the risk of VT El. Examining proteomic data from the United Kingdom Biobank, they also found no relationship between plasma plasminogen levels and VT El incidence. In summary, the authors found no apparent association between genetic loss or pharmacologic suppression of plasminogen activation and VT El formation in mice or humans. In humans, VT El risk was not increased by the presence of plasminogen pathway gene variants or by increased plasminogen protein levels. They concluded that plasminogen activation and plasmin activity play little or no role in regulating intravascular thrombus formation and routinely preventing VT El formation. These findings suggest that antifibrinolytic therapies might be used to treat bleeding without fear of raising the risk of VT El pending further investigation of more complex clinical scenarios. In an accompanying commentary, Andrew Yee of the Baylor College of Medicine in Houston, Texas, said that these findings lay important groundwork for a better understanding of how plasminogen activation and plasmin activity might be related to VT El formation in different conditions that lead to excess bleeding and when transexamic acid might be used to safely treat them. In the final part of today's podcast, we'll discuss findings in the Blood article entitled Transposable Elements as Novel Therapeutic Targets for PARP Inhibitor Induced Synthetic Lethality in PCG mutated blood cancer By Bernd Zeissig of King's College London and colleagues. Cancers that arise from loss of function mutations are challenging to target therapeutically. Proteins that already have lost their function cannot be targeted with therapies whose mechanisms involve inhibition, for example by enzymatic inhibitors. Hematological malignancies often carry loss of function mutations in the Polycomb epigenetic regulators EZH2 and ASXL1. These mutations are associated with poor patient prognosis, especially when they occur together. In addition to the difficulty of targeting loss of function mutations, development of therapies to treat malignancies carrying these mutations has been hindered by a lack of appropriate disease models. The authors of the third paper we're discussing developed mouse models to address this need, using primary samples from human patients to support the resulting mechanistic insights. For their model, they created transgenic mice in which the genes encoding ezh2 and asxl1 could be inducibly knocked out. Ezh2 and asxl1 are Polycomb group or PCG epigenetic regulators that control expression of specific genes in hematopoietic stem cells. Loss of function mutations in these genes are common in human blood malignancies, especially in myelodysplastic syndromes or mds. Bone marrow cells from mice carrying the inducible double knockout were transplanted into lethally irradiated mice. After induction. The transplanted mice showed abnormalities in the types and numbers of hematopoietic stem cells they produced over time. Nearly all of these mice developed aggressive MDS or myeloproliferative neoplasms similar to those seen in human patients carrying the EZH2 and ASXL1 mutations. Some of the double knockout transplanted mice also developed aggressive B cell malignancies, including a malignancy similar to human chronic lymphocytic leukemia or cll. The authors used gene expression analyses to gain insight into the pathways affected by EZH2ASXL1 double knockout in mice. In addition to activation of oncogenic pathways and suppression of apoptosis, they found that multiple DNA damage repair or DDR pathways were activated. This finding suggested that the mutated cells were experiencing excessive DNA damage. In other cancers, dysregulation of DDR pathways can be targeted using PARP inhibitors, leading the authors to further investigate the underlying mechanism of this DNA damage response. They found that excessive DNA damage was occurring as a result of the reactivation of transposable elements, or tes. Tes are movable DNA elements that make up nearly half of the human genome where they are normally kept in check by epigenetic mechanisms. When epigenetic mechanisms are compromised, TE activation can lead to deleterious changes in gene expression, aberrant immune responses, and DNA damage. Reactivated tes can be repaired and reintegrated into the genome by a process known as target site primed reverse transcription. This process depends on PARP activity, suggesting a vulnerability to PARP inhibitors via synthetic lethality. In fact, the EZH2ASXL1 double knockout cells turned out to be highly sensitive to the PARP inhibitors olaparib, veliparib and talazoparib. This sensitivity could be reversed by the reverse transcriptase inhibitors didenosine and lamovudine, supporting the link between target site primed reverse transcription and PARP sensitivity. Turning to primary cells from human malignancies, the authors found that both TE reactivation and DNA damage repair pathways were upregulated in MDS cells from a patient carrying the EZH2ASXL1 double mutation. When they compared human CLL patient samples with and without ASXL1 mutations, they found that the ASXL1 mutated cells showed both TE activation and DDR pathway upregulation, while the non ASXL1 cells did not. The ASXL1 mutated CLL cells also showed excessive DNA damage with PARP inhibitor treatment that could be partially reversed using reverse transcriptase inhibitors. Overall, the authors concluded that loss of the epigenetic function carried out by EZH2 and ASXL1 led to TE reactivation in both the engineered mice and cells from human patients with EZH2 and or ASXL1 mutated MDS or CLL. TE reactivation caused DNA damage and upregulated DDR pathways, creating a previously unappreciated synthetic vulnerability to PARP inhibitors that could potentially be exploited for treatment of patients with malignancies carrying these mutations. While not identical, this vulnerability is similar to the vulnerability created by loss of function BRCA mutations in solid tumors such as breast and ovarian cancer. In an accompanying commentary, Irini Trompucci of the Universite Cote d' Azur in Nice, France, said that the vulnerability to PARP inhibitors created by TE reactivation might be a promising strategy for extending PARP inhibitor use beyond the classical BRCA mediated mechanism for synthetic lethality. She said that further study will be needed to better understand the causal role of TE activation, clinical research, identify downstream sensor elements, and define tumor specific contexts that will support this therapeutic mechanism. For a list of additional authors as well as more detailed articles and commentaries on which this podcast is based. Please go to bloodjournal.org be sure to join us next week for another episode of Blood Podcast. Thank you for listening.