Summary
Malignant cells infiltrating the bone marrow (BM) interfere with normal cellular behaviour of supporting cells, thereby creating a malignant niche. We found that CXCR4‐receptor expression was ...increased in paediatric precursor B‐cell acute lymphoblastic leukaemia (BCP‐ALL) cells compared with normal mononuclear haematopoietic cells (P < 0·0001). Furthermore, high CXCR4‐expression correlated with an unfavourable outcome in BCP‐ALL (5‐year cumulative incidence of relapse ± standard error: 38·4% ± 6·9% in CXCR4‐high versus 12% ± 4·6% in CXCR4‐low expressing cases, P < 0·0001). Interestingly, BM levels of the CXCR4‐ligand (CXCL12) were 2·7‐fold lower (P = 0·005) in diagnostic BCP‐ALL samples compared with non‐leukaemic controls. Induction chemotherapy restored CXCL12 levels to normal. Blocking the CXCR4‐receptor with Plerixafor showed that the lower CXCL12 serum levels at diagnosis could not be explained by consumption by the leukaemic cells, nor did we observe an altered CXCL12‐production capacity of BM‐mesenchymal stromal cells (BM‐MSC) at this time‐point. We rather observed that a very high density of leukaemic cells negatively affected CXCL12‐production by the BM‐MSC while stimulating the secretion levels of granulocyte colony‐stimulating factor (G‐CSF). These results suggest that highly proliferative leukaemic cells are able to down‐regulate secretion of cytokines involved in homing (CXCL12), while simultaneously up‐regulating those involved in haematopoietic mobilization (G‐CSF). Therefore, interference with the CXCR4/CXCL12 axis may be an effective way to mobilize BCP‐ALL cells.
Summary
Malignant cells infiltrating the bone marrow (
BM
) interfere with normal cellular behaviour of supporting cells, thereby creating a malignant niche. We found that
CXCR
4‐receptor expression ...was increased in paediatric precursor B‐cell acute lymphoblastic leukaemia (
BCP
‐
ALL
) cells compared with normal mononuclear haematopoietic cells (
P
<
0·0001). Furthermore, high
CXCR
4‐expression correlated with an unfavourable outcome in
BCP
‐
ALL
(5‐year cumulative incidence of relapse ± standard error: 38·4% ± 6·9% in
CXCR
4‐high
versus
12% ± 4·6% in
CXCR
4‐low expressing cases,
P
<
0·0001). Interestingly,
BM
levels of the
CXCR
4‐ligand (
CXCL
12) were 2·7‐fold lower (
P
=
0·005) in diagnostic
BCP
‐
ALL
samples compared with non‐leukaemic controls. Induction chemotherapy restored
CXCL
12 levels to normal. Blocking the
CXCR
4‐receptor with Plerixafor showed that the lower
CXCL
12 serum levels at diagnosis could not be explained by consumption by the leukaemic cells, nor did we observe an altered
CXCL
12‐production capacity of
BM
‐mesenchymal stromal cells (
BM
‐
MSC
) at this time‐point. We rather observed that a very high density of leukaemic cells negatively affected
CXCL
12‐production by the
BM
‐
MSC
while stimulating the secretion levels of granulocyte colony‐stimulating factor (G‐
CSF
). These results suggest that highly proliferative leukaemic cells are able to down‐regulate secretion of cytokines involved in homing (
CXCL
12), while simultaneously up‐regulating those involved in haematopoietic mobilization (G‐
CSF
). Therefore, interference with the
CXCR
4/
CXCL
12 axis may be an effective way to mobilize
BCP
‐
ALL
cells.
Background
Regular colonoscopic surveillance for detection of dysplasia is recommended in longstanding inflammatory bowel disease (IBD), however, its sensitivity is disputed. Screening accuracy may ...increase by using a biomarker-based surveillance strategy.
Methods
A case-control study was performed to determine the prognostic value of DNA ploidy and p53 in IBD-related neoplasia. Cases with IBD-related colorectal cancer (CRC), detected in our surveillance program between 1985-2008, were selected and matched with two controls, for age, gender, disease characteristics, interval of follow-up, PSC, and previous surgery. Biopsies were assessed for DNA ploidy, p53, grade of inflammation and neoplasia. Progression to neoplasia was analyzed with Cox regression analysis, adjusting for potentially confounding variables.
Results
Adjusting for age, we found statistically significant Hazard ratios (HR) between development of CRC, and low grade dysplasia (HR5.5; 95%CI 2.6-11.5), abnormal DNA ploidy (DNA index (DI) 1.06-1.34, HR4.7; 95%CI 2.9-7.8 and DI>1.34, HR6.6; 95%CI 3.7-11.7) and p53 immunopositivity (HR3.0; 95%CI 1.9-4.7) over time. When adjusting for all confounders, abnormal DNA ploidy (DI 1.06-1.34, HR4.7; 95%CI 2.7-7.9 and DI>1.34, HR5.0; 95%CI 2.5-10.0) and p53 immunopositivity (HR1.7; 95%CI 1.0-3.1) remained statistically significant predictive of neoplasia.
Conclusion
In longstanding IBD, abnormal DNA ploidy and p53 immunopositivity are important risk factors of developing CRC. The yield of surveillance may potentially increase by adding these biomarkers to the routine assessment of biopsies.
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