Gene expression analysis after BTK and PI3Kδ inhibitor treatment in chronic lymphocytic leukemia identifies cell-surface CXCR4 as a synergistic target for combinatorial therapy - Report - MDSpire
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Analysis of Gene Expression Following Treatment with BTK and PI3Kδ Inhibitors in Chronic Lymphocytic Leukemia Reveals CXCR4 as a Potential Target for Combination Therapy

  • By

  • Gabriela Mladonicka Pavlasova

  • Veronika Sandova

  • Laura Ondrisova

  • Vaclav Seda

  • Petra Pavelkova

  • Daniel Filip

  • Krystof Hlavac

  • Josef Vecera

  • Sarka Pospisilova

  • Anna Panovska

  • Stacey M. Fernandes

  • Michael Doubek

  • Jennifer R. Brown

  • Marek Mraz

  • September 25, 2026

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Clinical Report: Gene Expression Changes in CLL with BTK and PI3Kδ Inhibitors

Overview

This study analyzes gene expression alterations in chronic lymphocytic leukemia (CLL) cells following treatment with BTK and PI3Kδ inhibitors, highlighting the similarities in gene expression changes induced by both inhibitors.

Background

Chronic lymphocytic leukemia (CLL) is characterized by the activation of the B-cell receptor (BCR) signaling pathway, making it a critical target for therapy. BTK and PI3Kδ inhibitors are effective treatments, but their impact on gene expression requires further exploration.

Data Highlights

TreatmentNumber of mRNAs Altered
Ibrutinib225
Idelalisib340

Key Findings

  • Both BTK and PI3Kδ inhibitors significantly alter gene expression in CLL cells.
  • 225 mRNAs were altered with ibrutinib and 340 with idelalisib (adjusted P < 0.05).
  • 105 differentially expressed mRNAs were shared between the two treatments.
  • Both inhibitors suppressed JAK-STAT signaling and activated the MAPK pathway.
  • BTKi/PI3Ki treatment decreased the proportion of activated, proliferative CXCR4dimCD5bright cells.
  • CXCR4 was identified as a potential target for combination therapy.

Clinical Implications

Understanding the gene expression changes can inform treatment strategies.

Conclusion

This analysis provides insights into the gene expression changes induced by BTK and PI3Kδ inhibitors in CLL.

Related Resources & Content

  1. Blood Cancer Journal, 2022 -- B Cell Receptor Signaling Regulates APOBEC3 Expression Through Direct Enhancer Interaction in B Cells Affected by Chronic Lymphocytic Leukemia
  2. Blood Cancer Journal, 2021 -- Targeting mTORC1/2 Protein Kinase Complexes Selectively Induces Antileukemic Responses Both In Vitro and In Vivo
  3. ASCO Publications — Network analysis to reveal BTK as a link between myeloid and T cells in TLR signaling in colorectal cancer.
  4. ASCO Publications — Initial results of the combination of PI3Kδ inhibitor zandelisib (ME-401) and the BTK inhibitor zanubrutinib in patients (pts) with relapsed or refractory (R/R) B-cell malignancies.
  5. NCCN Guidelines® Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2026
  6. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma
  7. https://pure.amsterdamumc.nl/ws/portalfiles/portal/150099169/Esmo-clinical-practice-guideline-interim-update-on-new-targeted-therapies-in-the-first-line-and-at-relapse-of-chronic-ly.pdf
  8. Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial - PMC
  9. Sustained benefit of zanubrutinib vs ibrutinib in patients with R/R CLL/SLL: final comparative analysis of ALPINE - PMC
  10. Chronic Lymphocytic Leukemia Treatment (PDQ®) - NCI
  11. Zanubrutinib for the treatment of patients with del(17p) and/or TP53 CLL/SLL: analysis across clinical studies - PubMed
  12. Oncology (Cancer)/Hematologic Malignancies Approval Notifications | FDA
  13. Lilly's Jaypirca (pirtobrutinib) significantly reduced the risk of disease progression or death by 45% when added to a venetoclax time-limited regimen in people with previously treated CLL/SLL | Eli Lilly and Company
  14. Fixed-Duration Triplet Therapy Demonstrates Efficacy for Patients with Relapsed/Refractory CLL | Dana-Farber Cancer Institute
  15. FDA warns about possible increased risk of death and serious side effects with cancer drug Copiktra (duvelisib)
  16. The Saga of Phosphatidylinositol 3-Kinase (PI3K) Inhibitors - 05/12/2022 | FDA
  17. Chronic Lymphocytic Leukemia: Disease Biology - PMC
  18. B cell receptor signaling and associated pathways in the pathogenesis of chronic lymphocytic leukemia - PMC

Original Source(s)

Gene expression analysis after BTK and PI3Kδ inhibitor treatment in chronic lymphocytic leukemia identifies cell-surface CXCR4 as a synergistic target for combinatorial therapy

  • by Gabriela Mladonicka Pavlasova, Veronika Sandova, Laura Ondrisova, Vaclav Seda, Petra Pavelkova, Daniel Filip, Krystof Hlavac, Josef Vecera, Sarka Pospisilova, Anna Panovska, Stacey M. Fernandes, Michael Doubek, Jennifer R. Brown, Marek Mraz

  • September 25, 2026

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