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* CHRU de Tours, Laboratoires d’Hématologie et d’Immunologie et Service d’Hématologie et Thérapie Cellulaire;
Université François Rabelais de Tours, équipes EA-3853 et EA-3855; and
¶ Inserm, équipe ESPRI "Microenvironnement de l’hématopoïèse et cellules souches," Tours, France
1Correspondence: Laboratoire d’Hématologie/Equipe Inserm ESPRI-EA3855, CHRU-Hôpital Bretonneau, 2 bd Tonnelle, Tours Cedex F-37044, France. E-mail: olivier.herault{at}med.univ-tours.fr
SPECIFIC AIMS
Acute myeloid leukemia (AML) is characterized by uncontrolled proliferation within the bone marrow of blast cells arrested in their maturation process. Peripheral blood blast (PBB) counts and the number of extramedullar tumor sites are extremely variable from one patient to another. The chemokine stromal-derived factor (SDF)-1 and its receptor CXCR4 regulate the trafficking of many cancer cells, including those of solid tumors and hematological malignancies. There is also growing evidence that SDF-1 has a pivotal role in the regulation of trafficking of normal hematopoietic progenitor cells (HPCs) and their homing/retention in bone marrow, and the mechanisms of blast dissemination could mimic those involved in the egress of normal HPCs from bone marrow during mobilization. The granulocyte colony-stimulating factor-induced mobilization process of HPCs is associated with a decrease in medullary levels of SDF-1 and up-regulation of CXCR4, and our group has reported an association between the mobilizing capacity of HPC and a single nucleotide polymorphism in CXCL12 (CXCL12 G801A), the SDF-1-encoding gene. The ability of blasts to exit from the bone marrow microenvironment, circulate in the peripheral blood, and anchor in extramedullar locations might thus depend on the CXCL12 genotype. The purpose of our study was to determine whether CXCL12 G801A polymorphism is critical for the dissemination of malignant cells in de novo AML.
PRINCIPAL FINDINGS
1. Frequency of the CXCL12 801A allele in de novo AML patients
Eighty-six consecutive adult Caucasian patients with newly diagnosed de novo AML and 100 healthy volunteers were included in this study after obtaining informed consent and approval by the ethics committee of the University Hospital of Tours. The French-American-British (FAB) cooperative group classification was applied to define the AML subtype and because of the heterogeneity, statistical analyses were performed grouping myeloid (FAB M0/M1/M2) and (myelo)monocytic subtypes (FAB M4/M5). CXCL12 G801A polymorphism was determined with a polymerase chain reaction (PCR)-restriction fragment length polymorphism assay (PCR-RFLP; Fig. 1
a), and the frequency of the 801A allele in our group of patients (7% A/A and 36% A/G) was the expected value for Caucasians and was not different from those among healthy volunteers. Moreover the frequencies of this allele were similar in FAB groups (41% and 46% in M0-M1-M2 and M4-M5 groups, respectively).
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2. Peripheral blood blast count and CXCL12 G801A polymorphism
Blast dissemination was evaluated by PBB count. The PBB count was not statistically influenced by FAB subtype [4.2 (0–94.1) and 10.3 (0–137.1) PBB/µl in M0-M1-M2 and M4-M5 groups, respectively]. It was correlated with the percentage of blasts in the bone marrow compartment (correlation coefficient 0.356, P<0.001), which was not different in 801A carriers (801A/A and 801A/G patients) and 801G/G patients [80 (23–98)% and 76 (17–98)%, respectively]. As presented in Fig. 2
, the presence of the 801A allele was associated with an increased PBB count when comparing 801A carriers to 801G/G patients [10.4 (0.1–94.1) and 2.6 (0–137.1) PBB/µl, respectively, P=0.031].
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3. Extramedullar tumor sites and CXCL12 G801A polymorphism
Tissue infiltration was evaluated by the presence of at least one extramedullar tumor site (lymph nodes, liver, spleen, skin, gums, testicles, Waldeyer ring, vertebrae, and nervous system). Since all patients were treated in the same hospital, clinical data were homogeneous. CXCL12 801A carrier status was highly associated with extramedullar locations, which were found in 51.4% of 801A carriers (66.7 and 48.4% of A/A and A/G patients, respectively) and in 26.5% of 801G/G patients (Fig. 2)
, with an odds ratio of 2.92 (95% confidence interval 1.18–7.21). These results were reinforced by a multivariate analysis showing that the independent variables associated with risk of extramedullar tumor site(s) were PBB count (P=0.012), age (P=0.029), and CXCL12 G801A polymorphism (P=0.042).
4. CXCR4 expression on marrow blast cells and leukemic dissemination in CXCL12 801A carriers
The expression of CXCR4 on the surface of bone marrow blasts was determined by flow cytometry (Fig. 1b
). CXCR4 expression was not statistically different between FAB groups [1.7 (1–28) and 2.9 (1–37.4) in M0-M1-M2 and M4-M5 groups, respectively] or between patients with and without extramedullar locations [S/N=2.2 (1–37.4) and 2.2 (1–11.6), respectively]. Considering CXCL12 G801A polymorphism, CXCR4 expression was correlated with PBB count in 801A carriers (correlation coefficient 0.546, P=0.001), whereas such a correlation could not be evidenced in 801G/G patients (correlation coefficient 0.176).
CONCLUSIONS AND SIGNIFICANCE
The significance of single nucleotide polymorphisms (SNPs) in cancer is a recent concept. For example, SNPs are involved in the clinical presentation of malignant diseases, e.g., SNP of vascular endothelial growth factor (VEGF) in melanomas, and in the therapeutic response, e.g., SNP of FCGR3A in lymphomas. In this study, we report a genetic determinant associated with the risk of metastasis.
Malignant cell migration, which is recognized as a critical step in metastasis, is a complex process mainly involving metalloproteases, adhesion molecules, and chemokines such as SDF-1. Recent reports indicate that the SDF-1/CXCR4 interaction may be important for the metastasis of solid tumors that express CXCR4. SDF-1 is the major chemokine released by the bone marrow microenvironment. It is encoded by the CXCL12 gene, and our study demonstrates that the CXCL12 801A allele is an independent risk factor for distant tissue infiltration by malignant cells in AML, concomitant with a higher circulating malignant cell count (Fig. 3
). These results are supported by our previous findings concerning mobilization of normal HPC and by the recent description of a higher frequency of splenomegaly and hepatomegaly in patients with chronic lymphocytic leukemia carrying this variant than in patients homozygous for the common genotype.
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The functional significance of this polymorphism has not been characterized. It could be associated with lower secretion of SDF-1, a hypothesis supported by the description of lower SDF-1 level in the plasma of normal homozygous 801A subjects and in stromal layer supernatants of long-term marrow cultures established from 801A carriers patients suffering from lymphoid malignancies. This decreased production of SDF-1 might explain the increased capability of malignant cells to egress from the bone marrow microenvironment. In this context, the correlation observed between CXCR4 expression on bone marrow blasts and the PBB count observed in A carrier patients might result from weaker SDF-1-induced down-regulation of this receptor, which is not sufficiently effective to hold back the malignant cells in the marrow compartment.
In conclusion, we report that CXCL12 G801A polymorphism is a genetic determinant involved in the clinical presentation of leukemia. This description of increased release of blasts from the bone marrow to the blood and higher frequency of distal dissemination in 801A carriers is the first report of an association between this polymorphism and the risk of tissue infiltration by malignant cells. It would be interesting to determine whether 801A carriers had reduced overall survival and a greater risk of recurrence of AML. Moreover, as the SDF-1/CXCR4 axis is involved in the migration process of various types of cancer cells, it could be hypothesized that the 801A variant constitutes a general risk factor for metastasis development and that assessment of CXCL12 G801A polymorphism should help in identifying patients at risk of metastasis. Further studies should clarify this question.
FOOTNOTES
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.05-5667fje
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