Compared with World Health Organization-defined acute myeloid leukaemia (AML) not otherwise specified, patients with AML with myelodysplasia-related changes (AML-MRC) are generally older and more likely to have poor-risk cytogenetics, leading to poor response and prognosis. More than one-half of all older (≥65 years) patients in the phase 3 AZA-AML-001 trial had newly diagnosed AML-MRC. We compared clinical outcomes for patients with AML-MRC treated with azacitidine or conventional care regimens (CCR; induction chemotherapy, low-dose cytarabine, or supportive care only) overall and within patient subgroups defined by cytogenetic risk (intermediate or poor) and age (65–74 years or ≥75 years). The same analyses were used to compare azacitidine with low-dose cytarabine in patients who had been preselected to low-dose cytarabine before they were randomized to receive azacitidine or CCR (ie, low-dose cytarabine). Median overall survival was significantly prolonged with azacitidine (n = 129) versus CCR (n = 133): 8.9 versus 4.9 months (hazard ratio 0.74, [95%CI 0.57, 0.97]). Among patients with intermediate-risk cytogenetics, median overall survival with azacitidine was 16.4 months, and with CCR was 8.9 months (hazard ratio 0.73 [95%CI 0.48, 1.10]). Median overall survival was significantly improved for patients ages 65–74 years treated with azacitidine compared with those who received CCR (14.2 versus 7.3 months, respectively; hazard ratio 0.64 [95%CI 0.42, 0.97]). Within the subgroup of patients preselected to low-dose cytarabine before randomization, median overall survival with azacitidine was 9.5 months versus 4.6 months with low-dose cytarabine (hazard ratio 0.77 [95%CI 0.55, 1.09]). Within the low-dose cytarabine preselection group, patients with intermediate-risk cytogenetics who received azacitidine had a median overall survival of 14.1 months versus 6.4 months with low-dose cytarabine, and patients aged 65–74 years had median survival of 14.9 months versus 5.2 months, respectively. Overall response rates were similar with azacitidine and CCR (24.8% and 17.3%, respectively), but higher with azacitidine versus low-dose cytarabine (27.2% and 13.9%). Adverse events were generally comparable between the treatment arms. Azacitidine may be the preferred treatment for patients with AML-MRC who are not candidates for intensive chemotherapy, particularly patients ages 65–74 years and those with intermediate-risk cytogenetics. This study was registered at clinicalTrials.gov on February 16, 2010 ( NCT01074047 ).

Acute myeloid leukemia (AML) is a heterogeneous neoplasm of the bone marrow with poor prognosis. In clinical practice new prognostic factors are still needed. MicroRNAs (miRs), small endogenous noncoding RNAs, play an essential role in the development and progression of acute leukemia. The aim of the study was to evaluate miR-204 expression in patients with AML at diagnosis and after induction chemotherapy, in comparison to healthy controls. We also investigated, if miR-204 expression correlates with clinical features of AML patients. miR-204 expression has been analyzed using RT-PCR in 95 bone marrow specimens from newly diagnosed AML patients in comparison to 20 healthy subject. We showed down-regulated miR-204 expression in AML patients, which was associated with shorter patients’ survival. Higher expression of miR-204 in patients after induction therapy was correlated with complete remission achieving. We showed low miR-204 expression in AML and found it to be an independent prognostic factor in this patient population.

MicroRNAs (miRs) are small non‑coding RNAs that play important roles in cell differentiation and survival. Abnormal expression of miRs has been demonstrated in numerous types of cancer, including acute myeloid leukaemia (AML). The aim of the present study was to evaluate miR‑181 expression at diagnosis and following the completion of chemotherapy in AML patients, with regard to clinical response and outcome, particularly in patients treated with azacitidine. miR‑181 expression was analysed using reverse transcription‑quantitative polymerase chain reaction in 95 bone marrow specimens from newly diagnosed AML patients and in 20 healthy subjects for comparison. The results revealed upregulated miR‑181 expression in the total cohort of AML patients, which was correlated with longer survival. However, in a subset of older AML patients treated with azacitidine, low miR‑181 expression at diagnosis was a predictor for complete remission and prolonged survival. The findings indicated that miR‑181 has an important role in AML and determines response to azacitidine treatment in older AML patients.

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10⁻⁹) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10⁻⁴−5.79 × 10⁻¹⁴). Mechanistically, we found that the ULK4_rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10⁻⁴), whereas the IKBKE_rs17433804 SNP correlated with the number of transitional CD24⁺CD38⁺ B cells (p = 4.8 × 10⁻⁴) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10⁻⁴). We also found that the CD46_rs1142469 SNP correlated with numbers of CD19⁺ B cells, CD19⁺CD3⁻ B cells, CD5⁺IgD⁻ cells, IgM⁻ cells, IgD⁻IgM⁻ cells, and CD4⁻CD8⁻ PBMCs (p = 4.9 × 10⁻⁴−8.6 × 10⁻⁴) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2A_rs2811710 SNP correlated with levels of CD4⁺EMCD45RO⁺CD27⁻ cells (p = 9.3 × 10⁻⁴). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3⁻, MCP-2⁻, and IL20-dependent pathways.

Clinical response to azacitidine therapy depends on microRNA-29c (miR-29c) expression in older acute myeloid leukemia (AML) patients

Multiple myeloma (MM) is a haematologic malignancy characterized by the presence of atypical plasma cells. Basigin (BSG, CD147) controls lactate export through the monocarboxylic acid transporter 1 (MCT1, SLC16A1) and supports MM survival and proliferation. Additionally, BSG is implicated in response to treatment with immunomodulatory drugs (thalidomide and its derivatives). We investigated the role of single nucleotide polymorphisms (SNPs) in the gene coding for BSG and SLC16A1 in MM. Following an in silico analysis, eight SNPs (four in BSG and four in SLC16A1) predicted to have a functional effect were selected and analyzed in 135 MM patients and 135 healthy individuals. Alleles rs4919859 C, rs8637 G, and haplotype CG were associated with worse progression-free survival (p = 0.006, p = 0.017, p = 0.002, respectively), while rs7556664 A, rs7169 T and rs1049434 A (all in linkage disequilibrium (LD), r² > 0.98) were associated with better overall survival (p = 0.021). Similar relationships were observed in thalidomide-treated patients. Moreover, rs4919859 C, rs8637 G, rs8259 A and the CG haplotype were more common in patients in stages II–III of the International Staging System (p < 0.05), while rs8259 A correlated with higher levels of β-2-microglobulin and creatinine (p < 0.05). Taken together, our results show that BSG and SLC16A1 variants affect survival, and may play an important role in MM.