No abstract

MicroRNAs belong to a class of small noncoding RNAs of ‫ف‬ 21 nt that control the expression of many genes ( 1, 2 ). MicroRNAs are preferentially transcribed by RNA polymerase II and can be derived from individual microRNA genes, introns of protein-coding genes, or polycistronic transcripts. They are fi rst transcribed as primary microRNAs (pri-microRNAs) that CORRESPONDENCE Pierre Brousset: brousset.p@chu-toulouse.fr C. Quelen and R. Rosati contributed equally to this paper. The online version of this article contains supplemental material. Most chromosomal translocations in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) involve oncogenes that are either up-regulated or form part of new chimeric genes. The t(2;11)(p21;q23) translocation has been cloned in 19 cases of MDS and AML. In addition to this, we have shown that this translocation is associated with a strong up-regulation of miR-125b (from 6-to 90-fold). In vitro experiments revealed that miR-125b was able to interfere with primary human CD34 + cell differentiation, and also inhibited terminal (monocytic and granulocytic) differentiation in HL60 and NB4 leukemic cell lines. Therefore, miR-125b up-regulation may represent a new mechanism of myeloid cell transformation, and myeloid neoplasms carrying the t(2;11) translocation defi ne a new clinicopathological entity. Myeloid cell diff erentiation arrest

JAK signaling pathway members in 27.7% of T-ALL samples screened; an observation with therapeutic potential. Statistically significant pairwise associations were found between different mutations, indicating the presence of functional interactions among different pathways in T-ALL pathogenesis. Of significance, we found a mutually exclusive relationship between IL7R-JAK mutations and the presence of TAL1/LMO2 rearrangements. We also identified positive correlations among IL7R-JAK mutations and mutations/deletions in PHF6 and members of the PRC2 complex. Our findings begin to unravel the diversity of genetic lesions that are implicated in the development of T-ALL. Methods DNA samplesT-ALL samples from patients (n=155: 111 children, 44 adults) were collected from various institutions (Online Supplementary Table S1). The diagnosis of T-ALL was based on morphology, cytochemistry and immunophenotyping according to World Health Organization criteria. Genomic DNA was isolated from bone marrow (either fixed or fresh bone marrow cells). 5,21,22 To investigate the prognostic relevance of IL7R, JAK1 and JAK3 mutations, Sanger sequencing was used to screen for mutations in these three genes in an independent cohort of 78 T-ALL patients. Those patients were all enrolled into the United Kingdom (UK) Children's Cancer and Leukaemia Group (CCLG) ALL2003 trial. 23This study was approved by the ethics committees of the institutes involved and informed consent was obtained from the participants. Samples and clinical data were stored in accordance with the declaration of Helsinki. Capture designSureDesign software was used to design two slightly different Haloplex capture assays (Table 1). The total amplicon number for design A was 23,127 with a region size of 472.006 kbp and a predicted target coverage of >99%. For design B the total amplicon number was 19,694 with a region size of 418.373 kbp and a predicted target coverage of >99%. For this study, 80 samples were processed with design A and 75 samples with design B. In both assays, the coding exons of selected genes (based on RefSeq, CCDS and VEGA databases) were targeted with an extra ten bases upstream and downstream. Targeted regions comprised the coding sequence of genes that were either recently identified as recurrently mutated in ALL or other hematologic malignancies (known driver genes) or were similar to known oncogenes (candidate driver genes) to be sequenced. 18,19,24,25 For statistical analyses we only considered the 115 genes that were sequenced in both Haloplex designs (Online Supplementary Table S2). Library preparation and sequencing were performed as described in the Online Supplementary Material. Data analysesIn NextGENe software (v2.2.1, Softgenetics, State College, PA, USA), we performed the following steps: (i) the fastQ output file was converted into a FASTA file to eliminate reads that were not "paired" and that did not meet the criteria of the default settings; (ii) reads from the converted unique FASTA file were aligned to the reference genome (...

Fusion between the NUP98 and NSD3 genes in a patient with acute myeloid leukemia associated with t(8;11)(p11.2;p15), is reported for the first time.