Specific microRNA (miRNA) signatures have been associated with different cytogenetic subtypes in acute leukemias. This finding prompted us to investigate potential associations between genetic abnormalities in multiple myeloma (MM) and singular miRNA expression profiles. Moreover, global gene expression profiling was also analyzed to find correlated miRNA gene expression and select miRNA target genes that show such correlation. For this purpose, we analyzed the expression level of 365 miRNAs and the gene expression profiling in 60 newly diagnosed MM patients, selected to represent the most relevant recurrent genetic abnormalities. Supervised analysis showed significantly deregulated miRNAs in the different cytogenetic subtypes as compared with normal PC. It is interesting to note that miR-1 and miR-133a clustered on the same chromosomal loci, were specifically overexpressed in the cases with t(14;16). The analysis of the relationship between miRNA expression and their respective target genes showed a conserved inverse correlation between several miRNAs deregulated in MM cells and CCND2 expression level. These results illustrate, for the first time, that miRNA expression pattern in MM is associated with genetic abnormalities, and that the correlation of the expression profile of miRNA and their putative mRNA targets is useful to find statistically significant protein-coding genes in MM pathogenesis associated with changes in specific miRNAs.

A previous report of the Programa de Estudio y Tratamiento de las Hemopatías IntroductionThe outcome of patients with acute promyelocytic leukemia (APL) has dramatically improved with the combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy, which has been adopted as the standard treatment for APL. 1 Using this combination, the cooperative group Programa de Estudio y Tratamiento de las Hemopatías Malignas (PETHEMA) reported that a risk-adapted strategy combining ATRA with anthracycline monochemotherapy for both induction and consolidation, followed by maintenance with ATRA and low-dose methotrexate and mercaptopurine (LPA99 trial), results in a higher antileukemic efficacy than in the previous LPA96 trial. 2 In this study, the improvement of the antileukemic efficacy was attributed to the novel addition of ATRA to consolidation therapy, combined with a moderate increase in the dose of anthracycline for patients with intermediate or high risk of relapse. 3 This benefit was coupled with a moderate toxicity and a high degree of compliance.To know if the advantage provided by a risk-adapted strategy including ATRA in consolidation therapy for intermediate-and high-risk APL patients is maintained long term, we have now performed an updated analysis of a significantly enlarged cohort of patients treated with the LPA99 protocol with more than 5-year median follow-up. The long-term outcome in these patients was compared with those treated with the LPA96 trial. MethodsThe eligibility criteria in this study were a diagnosis of de novo APL with demonstration of the t(15;17) or PML/RARA rearrangement, normal hepatic and renal function, no cardiac contraindication to anthracyclines, and Eastern Cooperative Oncology Group (ECOG) performance status less than 4. Informed consent was obtained from all patients. In accordance with the Declaration of Helsinki, the protocols were approved by the Research Ethics Board of each participating hospital.Details of laboratory studies for diagnosis, assessment of response, and molecular monitoring of minimal residual disease, as well as a complete description of the therapeutic management, are given elsewhere. 2,4 Briefly, induction therapy consisted of oral ATRA 45 mg/m 2 per day until morphologic complete remission (CR) and intravenous idarubicin 12 mg/m 2 on days 2, 4, 6, and 8. The idarubicin on day 8 was omitted for patients older than 70 years in the LPA99 protocol. For patients 20 years of age or younger, the ATRA dose was adjusted to 25 mg/m 2 . Patients in CR received For personal use only. on May 9, 2018. by guest www.bloodjournal.org From 3 monthly risk-adapted consolidation courses. In the LPA96 protocol, the first course consisted of idarubicin (5 mg/m 2 per day for 4 days), the second of mitoxantrone (10 mg/m 2 per day for 5 days), and the third of idarubicin (12 mg/m 2 per day for 1 day). From November 1, 1999 (LPA99 trial), intermediate-and high-risk patients, as previously defined, 3 received ATRA (45 mg/m 2 per day for 15 days) combined with ...

BackgroundFms-like tyrosine kinase-3 (FLT3) gene mutations are frequent in acute promyelocytic leukemia but their prognostic value is not well established. Design and MethodsWe evaluated FLT3-internal tandem duplication and FLT3-D835 mutations in patients treated with all-trans retinoic acid and anthracycline-based chemotherapy enrolled in two subsequent trials of the Results FLT3-internal tandem duplication and FLT3-D835 mutation status was available for 306 (41%) and 213 (29%) patients, respectively. Sixty-eight (22%) and 20 (9%) patients had internal tandem duplication and D835 mutations, respectively. Internal tandem duplication was correlated with higher white blood cell and blast counts, lactate dehydrogenase, relapse-risk score, fever, hemorrhage, coagulopathy, BCR3 isoform, M3 variant subtype, and expression of CD2, CD34, human leukocyte antigen-DR, and CD11b surface antigens. The FLT3-D835 mutation was not significantly associated with any clinical or biological characteristic. Univariate analysis showed higher relapse and lower survival rates in patients with a FLT3-internal tandem duplication, while no impact was observed in relation to FLT3-D835. The prognostic value of the FLT3-internal tandem duplication was not retained in the multivariate analysis. ConclusionsFLT3-internal tandem duplication mutations are associated with several hematologic features in acute promyelocytic leukemia, in particular with high white blood cell counts, but we were unable to demonstrate an independent prognostic value in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based regimens. monochemotherapy. Haematologica 2011;96(10):1470-1477. doi:10.3324/haematol.2011 This is an open-access paper.

Summary. Of 167 newly diagnosed acute promyelocytic leukaemia patients, 83 patients were long (L)-form (50%), eight variable (V)-form (5%) and 76 short (S)-form (45%). The V-form and S-form groups presented a significantly higher percentage of patients with white blood cell counts . 10 Â 10 9 /l (P , 0´05). The S-form cases displayed a significantly higher number of cases with M3v microgranular features (P 0´005) and CD34 expression (P , 0´0001). There were no differences between the three isoforms in complete remission (CR) rate (overall CR 90%), but the 3-year disease-free survival was lower for Vform cases than it was for L-and S-form cases (62% vs. 94% and 89%, P 0´056). We conclude that the V-form and Sform types are associated with some negative prognostic features at diagnosis. However, our data were only able to demonstrate an association with adverse prognosis in the Vform type and, moreover, as the number of cases was limited, needs to be confirmed in large, uniformly treated series.

Copy number analysis can be useful for assessing prognosis in diffuse large B cell lymphoma (DLBCL). We analyzed copy number data from tumor samples of 60 patients diagnosed with DLBCL de novo and their matched normal samples. We detected 63 recurrent copy number alterations (CNAs), including 33 gains, 30 losses, and nine recurrent acquired copy number neutral loss of heterozygosity (CNN-LOH). Interestingly, 20 % of cases acquired CNN-LOH of 6p21 locus, which involves the HLA region. In normal cells, there were no CNAs but we observed CNN-LOH involving some key lymphoma regions such as 6p21 and 9p24.1 (5 %) and 17p13.1 (2.5 %) in DLBCL patients. Furthermore, a model with some specific CNA was able to predict the subtype of DLBCL, 1p36.32 and 10q23.31 losses being restricted to germinal center B cell-like (GCB) DLBCL. In contrast, 8p23.3 losses and 11q24.3 gains were strongly associated with the non-GCB subtype. A poor prognosis was associated with biallelic inactivation of TP53 or 18p11.32 losses, while prognosis was better in cases carrying 11q24.3 gains. In summary, CNA abnormalities identify specific DLBCL groups, and we describe CNN-LOH in germline cells from DLBCL patients that are associated with genes that probably play a key role in DLBCL development.