Tumor Cell Dissemination and Tissue Infiltration Are Associated with CXCL12-G801A Polymorphism in De Novo Acute Myeloid Leukemia.
Authors: Herault Olivier , Dommange Florence , Espanel Claire , Domenech Jorge , Benboubker Lotfi , Ohresser Marc , Colombat Philippe , Binet Christian , Watier Herve , Cartron Guillaume 
Published: October 2019

Our group has reported an association between the mobilizing capacity of normal hematopoietic progenitor cells and polymorphism at position 801 (G to A transition) in CXCL12, the SDF-1-encoding gene (Benboubker et al, Br J Haematol 2001, 113: 247). The ability of leukemic cells to exit from the bone marrow microenvironment, circulate in the peripheral blood and anchor in extramedullary locations might thus depend on the CXCL12 genotype.

Eighty six Caucasian patients with newly diagnosed de novo AML were included in this study. Cytogenetic risk groups were classically defined as favourable (t(8;21), t(15;17) and inv(16)), unfavourable (−5, −7, del(5q), del(7q), abnormal 11q23 and complex karyotype) and intermediate (normal and all other structural/numerical abnormalities). Leukemic cell dissemination and tissue infiltration were evaluated by leukemic blood cell (LBC) count and the presence of at least one extramedullary tumor site. Genomic DNA was extracted from marrow samples and CXCL12-G801A- polymorphism was determined with a PCR-RFLP assay. The results were expressed as median [range] and number [percentage] of patients. Age, gender, FAB subtype, cytogenetic group, leukemic marrow cell percentage, LBC count, extramedullary tumor sites and CXCL12-G801A polymorphism were considered as variables in univariate analysis (Mann-Whitney U test, χ2 test and z-test for non-zero correlation). In order to evaluate the influence of independent factors on the risk of extramedullary tumor sites, a multivariate analysis was performed using the multiple regression method, including the variables with p<0.10 in the univariate tests. The level of significance was set at 0.05.

The LBC count was highly correlated with the leukemic marrow cell percentage (p=0.0007), which was not different in CXCL12-3′A carrier and G/G patients (80 [23–98]% and 76 [17–98]%, respectively, p=0.7239). Moreover, the presence of the CXCL12-3′A allele was associated with an increased LBC count when comparing CXCL12-3′A carriers to G/G patients (10.4 [0.1–94.1] vs 2.6 [0–137.1] LBC/mL, respectively, p=0.0309). The patients presenting extramedullary tumor site(s) were characterized by a lower mean age (39 [18–78] vs 53 [16–75] years, p=0.0050), a higher LBC count (10.9 [0.1–137.1] vs 2.5 [0–99.3] LBC/mL, p=0.0020), and a more frequent CXCL12-3′A allele (59.4% vs 33.3%, p=0.0184). CXCL12-3′A carrier status was indeed highly associated with extramedullary locations, which were found in 51.4% of CXCL12-3′A carriers (66.7% and 48.4% of A/A and A/G patients, respectively) and in 26.5% of G/G patients, with an odds ratio of 2.92 (95% CI 1.18–7.21). Age, LBC count, CXCL12-3′A carrier status and leukemic marrow cell percentages (87% [17–98] vs 75% [23–98] in patients presenting or not tissue infiltration, respectively, p=0.0904) were included in the multivariate analysis, and the independent variables found to be associated with risk of extramedullary tumor site(s) were LBC count (p=0.0122), age (p=0.0289) and CXCL12-G801A polymorphism (p=0.0416).

In conclusion, we report that CXCL12-G801A polymorphism is a genetic determinant involved in the clinical presentation of acute myeloid leukemia. This description constitutes the first report of an association between this polymorphism and the risk of tissue infiltration by tumor cells.