Polymorphism Of CD44 Influences Efficacy Of CD34+Cells Mobilization In Patients With Hematological Malignancies

In the last decade peripheral blood was the main source of hematopoietic stem cells (HSC) for autologous (auto-SCT) and allogeneic (allo-SCT) transplantation. The exact mechanisms of HSC mobilization are still not clear and efficacy of the procedure is hardly predictable. Numerous clinical factors including age, number of previous intensive regimens, radiotherapy and type of disease can influence efficacy of CD34+ cell mobilization for auto-SCT in patients with hematologic malignancies. Recently it has been stated that ligand- receptor interactions of adhesion molecules such as SDF1/CXCR4, VLA4/VCAM-1 or CD44/osteopontin play important role in homing of HSC in hematopoietic niche. There is evidence that disruption of the ligand-receptor complex leads to egress of HSC to peripheral blood. Influence of single nucleotide polymorphisms in CD44, VCAM-1 and CXCR4 on efficacy of HSC mobilization was evaluated in healthy donors, but not in patients with hematological disorders.

The aim of the present study was evaluation of constitutive polymorphism of genes encoding cytokines and receptors present in HSC niche and their impact on efficacy of mobilization of HSC in patients with hematological malignancies.

110 (60 females and 50 males) were enrolled to the study. The median age of the patients was 55 (range 22-69) years. All of the patients evaluated were eligible for autologous HSC mobilization and transplantation. The group consisted of patients with multiple myeloma (74), non-Hodgkin lymphoma (19), Hodgkin lymphoma (15) or acute myeloid leukemia (2). The mobilization procedures comprised chemotherapy and then G-CSF at a dose of 10µg/kg daily. ‘Poor mobilizers’ group was defined according to GITMO criteria: patients with peak CD34+ in peripheral blood < 20/μL or total yield <2x 10⁶ CD34+/kg in maximum 3 aphereses. Genotyping was performed using standard PCR-based assays. Three subgroups were established for the genotype in each polymorphism (homozygous more frequent, heterozygous and homozygous less frequent).

The group of patients (N=108) who achieved minimal threshold for collections (CD34+ at least 10/µl) proceeded to aphereses. Median total yield of CD34+ in this group of patients was 5,6 x 10^6//kg, while median number of cells collected during first apheresis was 3,3x 10^6//kg. Median number of days of G-CSF treatment before first apheresis was 10. Fifteen patients fulfilled the criteria for ‘poor mobilizer’.

The group of ‘poor mobilizers’ had higher frequency of TT allele in rs13347 (CD44) gene (CC+ CT vs TT p=0,047), the difference was even more pronounced in patients with multiple myeloma (N=72, p=0,027). TT homozygous genotype resulted in reduced CD44 mRNA expression at the time of apheresis in comparison with carries of C allele (median=40 in TT group, median=77 in CT and median=85 in CC group, p<0,001). Patients with TT allele had lower total yield CD34+/kg than the group with allele C (Median=3,7x 10^6//kg vs. 5,8x 10^6//kg, p=0.019) and lower number of CD34+cells gathered during first apheresis (0,95x 10^6//kg vs. 3,3x 10^6//kg, p=0.04). Multivariate logistic regression analysis including age, sex, diagnosis (multliple myeloma vs. others), number of previous treatment lines and CD44 polymorhism (TT vs CT+CC) revealed TT allele was the only factor associated with 5 fold higher risk of poor mobilization (p=0,037).

Polymorphic variants of CXCR4 and VCAM-1 did not influence significantly efficacy of HSC mobilization in our group of patients.

In conclusion, our results indicate that among investigated SNPs, only CD44 rs13347 has impact on efficacy HSC mobilization in patients with hematologic malignancies. CD44 SNPs analysis may be helpful for predicting of ‘poor mobilizers’ population that may benefit from newer modalities using adhesion molecules inhibitors.

No relevant conflicts of interest to declare.