Genetic Variants of ABC and SLC Transporter Genes and Chronic Myeloid Leukaemia: Impact on Susceptibility and Prognosis.

Solute carrier (SLC) and ATP-binding cassette (ABC) transporters comprise a variety of proteins expressed on cell membranes responsible for intrusion or extrusion of substrates, respectively, including nutrients, xenobiotics, and chemotherapeutic agents. These transporters mediate the cellular disposition of tyrosine kinase inhibitors (TKIs), and their genetic variants could affect its function, potentially predisposing patients to chronic myeloid leukaemia (CML) and modulating treatment response. We explored the impact of genetic variability (single nucleotide variants-SNVs) of drug transporter genes (ABCB1, ABCG2, SLC22A1, and SLC22A5) on CML susceptibility, drug response, and BCR-ABL1 mutation status. We genotyped 10 SNVs by tetra-primers-AMRS-PCR in 198 CML patients and 404 controls, and assessed their role in CML susceptibility and prognosis. We identified five SNVs associated with CML predisposition, with some variants increasing disease risk, including TT genotype ABCB1 (rs1045642), and others showing a protective effect (GG genotype SLC22A5 rs274558). We also observed different haplotypes and genotypic profiles associated with CML predisposition. Relating to drug response impact, we found that CML patients with the CC genotype (rs2231142 ABCG2) had an increased risk of TKI resistance (six-fold). Additionally, CML patients carrying the CG genotype (rs683369 SLC22A1) presented a 4.54-fold higher risk of BCR-ABL1 mutations. Our results suggest that drug transporters' SNVs might be involved in CML susceptibility and TKI response, and predict the risk of BCR-ABL1 mutations, highlighting the impact that SNVs could have in therapeutic selection.

MicroRNA signature refine response prediction in CML.

microRNAs (miRs) dysregulation have emerged as a crucial step in tumorigenesis, being related with cancer development, progression and response to treatment. In chronic myeloid leukaemia (CML), the resistance to tyrosine kinase inhibitors (TKI) is responsible for treatment failure and could be linked to changes in miRs expression. This work aimed to correlate the expression levels of 3 miRs, miR-21, miR-26b and miR-451, with response to TKI treatment in CML patients. miR-451 levels at diagnosis were significantly higher in patients with optimal response after 6 and 12 months of therapy. Conversely, patients without optimal response had highest levels of miR-21. miR-21 and miR-451 appear to be good biomarkers of response, able to predict optimal TKI responders (p < 0.05). Using the combined profile of both miRs, we create a predictive model of optimal response after one year of treatment. This study highlights the role of miR-21 and miR-451 expression levels at diagnosis in predicting which patients achieve the optimal response.

CD43 and CD49d from the B-Cell Chronic Lymphoproliferative Disorders Diagnostic Panel Are Useful to Detect Erythroid Dysplasia.

BACKGROUND: Despite bone marrow (BM) immunophenotyping by flow cytometry has progressively been recognized as an important tool for the diagnosis of myelodysplastic syndromes (MDS), the sparse knowledge about normal erythroid maturation and the lack of markers for erythroid characterization is a major shortcoming. METHODS: Here, we analyzed the expression of CD43 and CD49d, two markers included in the diagnostic panel for B-cell chronic lymphoproliferative disorders (B-CLPD), in the CD34+ compartment of normal BM and along the normal and dysplastic erythroid maturation. For this, 13 normal BM aspirates and 18 BM aspirates from MDS patients were studied by flow cytometry. RESULTS: Normal BM presented a higher expression of CD43 and CD49d among CD34+ erythroid precursors, compared to CD34+ cells committed to the remaining hematopoietic cell lineages. CD43 expression progressively decreased along the normal erythroid maturation, whereas CD49d levels increased from Stage I to Stage II, were maintained in Stages II and III, and then decreased until the last stage of maturation. In MDS, the expression of CD43 and CD49d followed a similar pattern, but with decreased expression levels for both markers, observed in all erythroid maturation stages (P < 0.05). CONCLUSIONS: Our results point to the usefulness of CD43 and CD49d, two markers commonly present in B-CLPD diagnosis panels, in the identification of dysplastic phenotypic features in the erythroid lineage. This allows a feasible and inexpensive way to identify patients who would benefit from a more extensive study to evaluate the presence of MDS, during the processing of suspected B-CLPD samples. © 2019 International Clinical Cytometry Society.

Quantification and phenotypic characterization of peripheral blood Vδ1 + T cells in chronic lymphocytic leukemia and monoclonal B cell lymphocytosis.

BACKGROUND: Vδ1+ T cells, a subset of γδ T cells, are responsible for innate-like immune responses. Recently, an anti-tumor function mediated by MHC-unrestricted recognition of lipid and stress molecules, has also been described in these cells. This study aimed to quantify and phenotypically characterize circulating Vδ1+ T cells in B cell Chronic Lymphocytic Leukemia (CLL) and Monoclonal B cell lymphocytosis (MBL). METHODS: This study enrolled 58 individuals distributed in five groups: Binet B and C CLL (n = 9), Binet A CLL (n = 26), High count-MBL (n = 10), Low count-MBL (n = 5), and a control group (n = 8). The phenotypic characterization of Vδ1+ T cells, as well as the other T cell subpopulations (CD4+ , CD8+ , CD4+ /CD8+ , and Vδ1- γδT cells), were assessed by flow cytometry, evaluating the frequency of each subset expressing CD27, CD69, and cytoplasmic granzyme B. RESULTS: We observed an increasing percentage of Vδ1+ T cells belonging to CD27- compartment from controls to advanced stages of the disease, which was accompanied by an increasing percentage of these cells expressing granzyme B, a phenotypic pattern that was also observed in the other T cell subpopulations under study since earlier stages of the disease. Moreover, a striking expansion of Vδ1+ T cells in Binet B and C CLL was observed. CONCLUSIONS: These experiment findings point to an expansion of CD27- Vδ1+ T cells with a cytotoxic profile, from controls to advanced stages of the disease, which points to a role of Vδ1+ T cells in the host's anti-tumor responses against clonal B-cells in MBL and CLL. © 2018 Clinical Cytometry Society.