Blood Podcast (American Society of Hematology)

Episode: DLBCL’s Long-Term Effects on Immune Profiles, Plasminogen Activation and VTE, and PARP Inhibitors in Epigenetically Mutated Hematological Malignancies

Date: September 11, 2025

Overview

This episode of the Blood Podcast delves into newly published research on three cutting-edge hematology topics:

• The lingering impact of diffuse large B-cell lymphoma (DLBCL) on immune system profiles years post-treatment
• The role of plasminogen activation in the prevention of venous thromboembolism (VTE)
• The emerging role of PARP inhibitors in hematological malignancies marked by epigenetic mutations, focusing on synthetic lethality via transposable element activity

The host offers clear explanations, highlights key findings, and shares expert commentary on the clinical and research implications of each study.

1. DLBCL Leaves a Lasting Mark on Immune System Function

Based on:
Palzel et al., University Hospital of Erlangen, Germany
[00:25 - 06:45]

Key Insights

• Persistent Immune Changes:
  Patients with DLBCL exhibit a “dysfunctional immune phenotype” at diagnosis, with higher activated T cells, increased immunosuppressive myeloid-derived suppressor cells (MDSCs), and decreased naive T cells. These immune alterations persist through treatment, remission, and even years after achieving remission.

• Long-Term Immune Dysregulation:
  Changes in immune cell populations endure well past “cure,” suggesting an “immune scar” unique to each cancer type. Even patients in complete remission for five years had immune profiles that more closely matched those with active disease than healthy controls.

• Broader Implications:
  Persistent dysregulation may elevate the risk for infections, autoimmune conditions, secondary malignancies, and may impact responses to immunotherapy or vaccinations.

• Disease-Specific Patterns:
  Immune dysregulation signatures differ among cancer types (DLBCL, chronic lymphocytic leukemia, acute myeloid leukemia, and breast cancer), with each leaving a distinct “immune scar.”

• Mouse Models Support Human Data:
  Mice injected with non-Hodgkin lymphoma cells developed immune alterations similar to human DLBCL patients.

Notable Quotes

• “The immune profiles of patients in remission from DLBCL more closely resembled those of patients with active lymphoma than they did those of healthy controls, even in patients who were in complete remission for five years or more.” [03:45]

• “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.” [05:20]

• “While cancer therapy may eradicate the tumor, it does not eradicate persistent changes in the immune system.” — Commentary by Michael Jain and Jonathan Couls Lartigue [06:02]

Timestamps

• [00:25] – Introduction to immune alterations in DLBCL
• [01:45] – Study design and major immunologic findings
• [03:45] – Immune disruption in remission
• [04:40] – DLBCL versus other cancers: unique “immune scars”
• [05:50] – Mouse model validation
• [06:02] – Expert commentary on implications

2. Plasminogen Activation: Not Critical for Routine Prevention of Venous Thromboembolism (VTE)

Based on:
Sang et al., University of North Carolina at Chapel Hill
[06:46 - 13:05]

Key Insights

• Fibrinolytic System Context:
  Plasminogen is converted to plasmin by tissue plasminogen activator (tPA), dissolving fibrin-rich clots. Standard therapy for clots (like stroke) involves harnessing this pathway.

• New Evidence Against a Routine Protective Role:
  Individuals with congenital plasminogen deficiency and mice genetically altered to lack plasminogen do not show increased rates of VTE or pulmonary embolism.

• Trial with Antifibrinolytic (Tranexamic Acid):
  Suppressing plasmin formation did not increase VTE risk in mouse models, nor did it alter clot size or composition.

• No Genetic Link in Humans:
  Large genome-wide association studies and proteomic data in humans show no association between plasminogen pathway variants or levels and VTE risk.

• Clinical Implication:
  Antifibrinolytic drugs can likely be used to treat bleeding without increasing VTE risk—pending further study in complex patient scenarios.

Notable Quotes

• “There was no history of VTE or pulmonary embolism in this patient population [with type 1 plasminogen deficiency].” [08:10]

• “They found no significant associations between variants in genes involved in the plasminogen activation pathway and the risk of VTE.” [11:22]

• “Plasminogen activation and plasmin activity play little or no role in regulating intravascular thrombus formation and routinely preventing VTE formation.” [12:40]

• “These findings lay important groundwork for a better understanding of how plasminogen activation and plasmin activity might be related to VTE formation in different conditions.” — Andrew Yee, commentary [13:02]

Timestamps

• [06:46] – Background: clot formation and fibrinolysis
• [07:45] – Plasminogen deficiency in humans: no increased VTE
• [09:15] – Mouse models and antifibrinolytic experiments
• [11:15] – Human studies: genetic and proteomic data
• [12:40] – Summary and implications
• [13:02] – Expert commentary

3. Transposable Elements and Synthetic Vulnerability to PARP Inhibitors in Blood Cancers with PCG Mutations

Based on:
Zeissig et al., King’s College London
[13:06 - 20:50]

Key Insights

• Therapeutic Challenge:
  Hematological malignancies often have loss-of-function mutations in Polycomb group (PCG) epigenetic regulators (EZH2, ASXL1), which are hard to target with standard inhibitors.

• New Mouse Models Provide Answers:
  Inducible knockout of EZH2 and ASXL1 in mice led to diseases closely resembling patient cases of MDS, myeloproliferative neoplasms, and CLL.

• Mechanism of Synthetic Lethality:
  Loss of epigenetic control led to reactivation of transposable elements (TEs), which in turn caused DNA damage and activated DNA damage repair (DDR) pathways. This process created reliance on PARP for cell survival.

• PARP Inhibitor Sensitivity:
  Double knockout cells (EZH2/ASXL1) were especially sensitive to PARP inhibitors (olaparib, veliparib, talazoparib), and this sensitivity could be reversed by blocking reverse transcriptase, confirming the mechanism.

• Clinical Implications:
  Human patient cells mirrored mouse findings, indicating a new rationale for using PARP inhibitors in epigenetically mutated hematological cancers—not just in the context of BRCA mutations.

Notable Quotes

• “The authors concluded that loss of the epigenetic function carried out by EZH2 and ASXL1 led to TE reactivation… creating a previously unappreciated synthetic vulnerability to PARP inhibitors.” [19:10]

• “This vulnerability is similar to the vulnerability created by loss of function BRCA mutations in solid tumors such as breast and ovarian cancer.” [19:50]

• “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.” — Irini Trompucci, commentary [20:15]

Timestamps

• [13:06] – Introduction: challenge of targeting PCG mutations
• [14:00] – Mouse models and parallels to human disease
• [15:50] – TE reactivation and DDR pathway upregulation
• [17:20] – Synthetic lethality via PARP inhibitor, mechanism confirmed
• [18:45] – Human patient samples affirm findings
• [19:50] – Clinical significance and analogy to BRCA mutations
• [20:15] – Commentary on future directions

Conclusion

This episode highlights research that challenges established assumptions (the limited role of plasminogen activation in VTE prevention), uncovers lasting consequences long after lymphoma treatment (persistent immune scars in DLBCL and other cancers), and illuminates novel therapeutic opportunities (exploiting transposable element reactivation for selective use of PARP inhibitors in hematological malignancies).

For more details and full articles, visit bloodjournal.org.