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Differential bone marrow homing capacity of VLA-4 and CD38 high expressing chronic lymphocytic leukemia cells
Gabriele Brachtl1, Karine Sahakyan, Ursula Denk
1Laboratory for Immunological and Molecular Cancer Research, Third Medical Department with Hematology, Oncology, Hemostaseology, Infectiology and Rheumatology, Private Medical University Hospital, Salzburg, Austria.
Insights
VLA-4 expression, not CD38, drives chronic lymphocytic leukemia (CLL) cell homing to bone marrow (BM) and infiltration. VLA-4 plays a key role in CLL cell recirculation and prognosis, with limited impact on stromal cell protection.
Area of Science:
- Hematology
- Immunology
- Cancer Biology
Background:
- Chronic lymphocytic leukemia (CLL) is characterized by poor prognosis predicted by VLA-4 and CD38 expression.
- Discordant VLA-4/CD38 risk profiles in CLL necessitate investigation into their individual roles.
- Understanding these roles is crucial for elucidating CLL cell behavior in bone marrow (BM) microenvironments.
Purpose of the Study:
- To determine the individual roles of VLA-4 and CD38 in chronic lymphocytic leukemia (CLL) bone marrow (BM) infiltration.
- To investigate the impact of VLA-4 and CD38 on CLL cell homing to murine BM.
- To assess the contribution of VLA-4 and CD38 to CLL cell-stromal cell interactions and survival.
Main Methods:
- Quantification of VLA-4, CD38, and Ki-67 expression in CLL cells from peripheral blood and BM.
- Correlation of CLL BM infiltration rates with VLA-4 and CD38 expression levels.
- Evaluation of CLL cell homing capacity via adoptive transfer experiments in murine models.
- Assessment of CLL cell viability and adhesion in co-culture with stromal cells.
Main Results:
- VLA-4, not CD38, was identified as the primary driver of CLL cell recirculation to murine BM.
- Higher VLA-4 expression correlated with increased human BM infiltration, independent of CD38 levels.
- Both VLA-4 and CD38 served as independent prognostic markers, with increased expression observed in BM-derived CLL cells.
- VLA-4 did not significantly enhance CLL cell protection by stromal cells in vitro.
Conclusions:
- VLA-4 expression plays a prominent role in the homing of CLL cells to BM niches and subsequent human BM infiltration.
- CD38 expression, while a prognostic marker, has a limited role in CLL cell homing and BM infiltration compared to VLA-4.
- The role of VLA-4 in CLL cell protection by stromal cells is limited, suggesting other mechanisms are involved in survival within the BM microenvironment.
Background:
VLA-4 and CD38 predict a poor clinical outcome in chronic lymphocytic leukemia (CLL). We used CLL samples with discordant VLA-4/CD38 risk to address their individual roles in human bone marrow infiltration (BM), CLL cell homing to murine BM, and in supportive CLL cell-stromal cell interactions.
Methods:
VLA-4, CD38, and Ki-67 expression was measured in CLL cells from peripheral blood (PB) and bone marrow (BM) aspirates. CLL BM infiltration rates, routinely determined by Pathology, were correlated to VLA-4 and CD38 expression. Short-term homing capacity of CLL cells was evaluated by adoptive transfer experiments. CLL cell viability and adhesion in stromal cell co-culture was determined.
Results:
About 20% of CLL samples in our cohort displayed discordant VLA-4 and CD38 risk, with either high VLA-4 and low CD38 risk or vice versa. Using particularly such samples, we observed that VLA-4, and not CD38, was responsible for recirculation of CLL cells to murine BM. Human BM infiltration was also significantly higher in patients with high VLA-4 risk but not high CD38 risk. However, both molecules acted as independent prognostic markers. While both VLA-4 and CD38 expression were increased in BM-derived CLL cells, and VLA-4+ and CD38+ subpopulations showed enriched Ki-67 expression, VLA-4 did not contribute to CLL cell protection by stromal cells in vitro.
Conclusions:
Our data argue for a prominent role of VLA-4 but not CD38 expression in the homing of CLL cells to BM niches and in human BM infiltration, but only a limited role in their protection by stromal cells.
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