Refinement of 1p36 Alterations Not Involving PRDM16 in Myeloid and Lymphoid Malignancies

Fluorescence in situ hybridization was performed to characterize 81 cases of myeloid and lymphoid malignancies with cytogenetic 1p36 alterations not affecting the PRDM16 locus. In total, three subgroups were identified: balanced translocations (N = 27) and telomeric rearrangements (N = 15), both mainly observed in myeloid disorders; and unbalanced non-telomeric rearrangements (N = 39), mainly observed in lymphoid proliferations and frequently associated with a highly complex karyotype. The 1p36 rearrangement was isolated in 12 cases, mainly myeloid disorders. The breakpoints on 1p36 were more widely distributed than previously reported, but with identifiable rare breakpoint cluster regions, such as the TP73 locus. We also found novel partner loci on 1p36 for the known multi-partner genes HMGA2 and RUNX1. We precised the common terminal 1p36 deletion, which has been suggested to have an adverse prognosis, in B-cell lymphomas [follicular lymphomas and diffuse large B-cell lymphomas with t(14;18)(q32;q21) as well as follicular lymphomas without t(14;18)]. Intrachromosomal telomeric repetitive sequences were detected in at least half the cases of telomeric rearrangements. It is unclear how the latter rearrangements occurred and whether they represent oncogenic events or result from chromosomal instability during oncogenesis

Restriction of Measles Virus RNA Synthesis by a Mouse Host Cell Line: trans-Complementation by Polymerase Components or a Human Cellular Factor(s)

The mouse epithelial MODE-K cell line expressing human CD46 or CD150 cellular receptors was found to be nonpermissive for measles virus (MV) replication. The virus binding and membrane fusion steps were unimpaired, but only very limited amounts of virus protein and RNA synthesized were detected after the infection. In a minigenome chloramphenicol acetyltransferase assay, MODE-K cells were as able as the permissive HeLa cells in supporting MV polymerase activity. The restriction phenotype of MODE-K cells could be alleviated by providing, in trans, either N-P-L or N-P functional protein complexes but not by P-L complexes or individual N, P, and L proteins. Several human × mouse (HeLa × MODE-K) somatic hybrid clones expressing human CD46 were isolated and found to be either nonpermissive or permissive according to their human chromosomal contents. The MV-restricted phenotype exhibited by the MODE-K cell line suggests that a cellular factor(s) can control MV transcription, possibly by stabilizing the incoming virus polymerase templates

Hematopoietic Progenitor Cell Response to SDF-1 alpha and SDF-1 alpha Production Are Impaired in Chronic Phase Chronic Myeloid Leukemia at Diagnosis.

Abstract SDF-1 alpha and its cognate receptor CXCR-4 are involved in normal Hematopoietic Progenitor Cells (HPC) regulation of adhesion, migration and survival. In Chronic Phase (CP) Chronic Myeloid leukaemia (CML), HPC exhibit a deregulation of all of those phenomena. Here, we investigated by different ways, the involvement of SDF-1 alpha in the pathogenesis of CP CML. Samples of bone marrow (BM) and peripheral blood (PB) from normal donors (ND) (n=10), CP CML (100% Ph1+ metaphases, all selected for Ph1+ LTC-IC) patients at diagnosis (n=35) and CP CML patients in Complete Cytogenetic Response (CCR) (0% Ph1+) (n=10) were explored. First, SDF-1 alpha concentrations were determined by ELISA assays in PB and BM samples, and showed higher yields for CP CML PB (2060±700 pg/ml) compared to CCR PB [1570±300 pg/ml (p=0.002)] and lower concentrations for CP CML BM (3080±1015 pg/ml) compared to CML in CCR BM [3990±680 pg/ml (p=0.01)] and ND BM [4060±1020 pg/ml (p=0.03)]. CCR BM and PB, and ND BM and PB SDF-1 alpha concentrations were not different. Further, we analyzed CD34+Lin− HPC migration in a 4h-Transwell™ assay, in SFM conditions ± SDF-1 alpha or ± one of its specific inhibitors SDF-1(G2) vs control. After migration, median percentages of migrating cells were consistently higher for CML vs ND BM (32±9 vs 20±1, p=0.002) in control arm, but equivalent for CML samples with SDF-1 alpha (39±10) vs control (32±9) indicating a relative insensitivity of CML HPC to this chemokine. In addition, SDF-1(G2) significantly inhibited the migration of CML HPCs (28±7) vs SDF-1 alpha (p=0.01). The proportion of CFC and LTC-IC in the migrating fraction was equivalent in the 3 experimental arms (SDF-1 alpha vs SDF-1(G2) vs control). As assessed by FACS, CD34+Lin− cells CXCR-4 surface expression was equivalent for CP CML (31±2.3%) and ND BM (43±2%) before migration, and there was no modification of the CXCR-4 expression after migration for CP CML. As SDF-1 alpha is involved in the regulation of the proliferation of normal HPC, we assessed CP CML CD34+Lin− cells in 3H-Thymidine cycling assays after 14 days culture on M210B4 murine feeder cell line (producing residual concentrations of SDF-1 alpha). CP CML HPC (CFC and LTC-IC) cycling status was not modified either after SDF-1 alpha or SDF-1(G2) exposure whereas ND BM cycling was paradoxically up-regulated by SDF-1(G2) vs control, suggesting a specific functional defect of CP CML HPCs in response to SDF-1 alpha. Taken together, all these results suggest that SDF-1 alpha production by stromal cells is impaired in CP CML, and that migratory and proliferative responses of CP CML HPCs to SDF-1 alpha are likely to be perturbed. This results might illustrate some pathologic interactions between BCR-ABL and signal transduction pathways activated through CXCR-4 ligation to its sole ligand SDF-1 alpha.</jats:p

Bone Marrow Necrosis in Newly Diagnosed Acute Leukemia: Two Case Reports and Review of the Literature

Article full text The full text of this article can be found here. https://link.springer.com/article/10.1007/s40487-017-0041-7 Provide enhanced content for this article If you are an author of this publication and would like to provide additional enhanced content for your article then please contact [email protected]. The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as ‘peer reviewed’ to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content. Other enhanced features include, but are not limited to: • Slide decks • Videos and animations • Audio abstracts • Audio slides</p

Prognostic Value of Immunophenotyping in Elderly Patients with Acute Myeloid Leukemia: A Single Institution Experience.

Abstract The poor prognosis of elderly patients with acute myeloid leukemia (AML) raises the question about the benefit of intensive chemotherapy in these patients. The impact of initial characteristics on prognosis has previously been addressed in elderly paitents, but very few data are available regarding the prognostic value of immunophenotypic characteristics in this setting. We investigated the expression of the membrane antigens CD13, CD15, CD33, and CD34 by flow cytometry in elderly patients with newly diagnosed AML, and analyzed whether these parameters possessed clinical or prognostic relevance, in order to help physicians in their choice of therapy. Immunophenotyping was performed in 273 patients aged 60 years or more (median 69 years). CD13 was expressed in 73%, CD15 in 43%, CD33 in 64%, and CD34 in 66% of cases. Complete remission was obtained in 157 cases (58%). The median overall survival was 8.1 months with a 3-year survival rate of 14%. Three risk groups were defined based on CD34 and CD33 antigen expression: Poor risk in patients with CD34+ CD33+ or CD34− CD33− disease, intermediate risk in patients with CD34+ CD33− disease, and favorable risk in patients CD34− CD33+ disease. Immunophenotype was, after cytogenetics, the most significant prognostic factor in terms of survival in a multivariate analysis (p = 0.03 and p &lt; 0.0001 respectively). When combining immunophenotypic and cytogenetic parameters, patients were classified into four prognostic groups: Group A (3-year survival: 33%) including favorable and normal karyotypes with a favorable immunophenotype; Group B (3-year survival: 28%) including normal karyotypes with an intermediate immunophenotype; Group C (3-year survival: 8%) including intermediate or normal karyotypes with an unfavorable immunophenotype; and Group D (3-year survival: 2%) including all unfavorable cytogenetics. Immunophenotypic characteristics appeared to be a major prognostic factor in this patient population. Using two simple parameters assessed at time of diagnosis, we devised a prognostic system of immediate clinical utility for prognostic stratification and risk-adapted therapeutic choices.</jats:p