Expression of CD43 in chronic lymphoproliferative leukemias.
Cytometry B Clin CytomJan 2018, 94(1)136-142. Epub 25 Jan 2017
CD43 has been used on histological samples for the differential diagnosis of lymphoproliferative disorders but there is scarce data on its use by flow cytometry (FC). We set out to characterize the expression of CD43 by FC in B-cell lymphoproliferative disorders and to determine its possible role in the differential diagnosis of these malignancies.
Motlló C, Ribera JM, Morgades M, Granada I, Montesinos P, Mercadal S, González-Campos J, Moreno MJ, Barba P, Cervera M, Barrios M, Novo A, Bernal T, Hernández-Rivas JM, Abella E, Amigo ML, Tormo M, Martino R, Lavilla E, Bergua J, Serrano A, García-Belmonte D, Guàrdia R, Grau J, Feliu E
Frequency and prognostic significance of additional cytogenetic abnormalities to the Philadelphia chromosome in young and older adults with acute lymphoblastic leukemia.
Leuk. LymphomaJan 2018, 59(1)146-154. Epub 30 May 2017
About 25-35% of adult patients with acute lymphoblastic leukemia show the Philadelphia (Ph) chromosome. Few series have evaluated the prognosis of additional cytogenetic alterations (ACA) to the Ph chromosome. We analyzed the frequency, type and prognostic significance ofACA in adults (18-60 years) treated in the ALL-Ph-08 trial. Fifty-two out of 74 patients (70%) showed ACA and 19 (26%) presented monosomies associated with t(9;22) (monosomal karyotype, MK). Similar complete response (CR) rate, CR duration, overall survival and event-free survival (EFS) were observed in patients with or without ACA, but patients with MK showed shorter CR duration and EFS than the remaining. On multivariate analysis, the only variable with prognostic impact for CR duration and EFS was the presence of MK (p = .003 and p = .036, respectively). Although ACA associated with the Ph chromosome are frequent, only monosomies were associated with poor prognosis in this group of patients.
Martínez-Cuadrón D, Montesinos P, Vellenga E, Bernal T, Salamero O, Holowiecka A, Brunet S, Gil C, Benavente C, Ribera JM, Pérez-Encinas M, De la Serna J, Esteve J, Rubio V, González-Campos J, Escoda L, Amutio ME, Arnan M, Arias J, Negri S, Lowënberg B, Sanz MA
Long-term outcome of older patients with newly diagnosed de novo acute promyelocytic leukemia treated with ATRA plus anthracycline-based therapy.
LeukemiaJan 2018, 32(1)21-29. Epub 6 Jun 2017
Treatment outcome in older patients with acute promyelocytic leukemia (APL) is lower compared with younger patients, mainly because of a higher induction death rate and postremission non-relapse mortality (NRM). This prompted us to design a risk- and age-adapted protocol (Programa Español de Tratamientos en Hematología (PETHEMA)/HOVON LPA2005), with dose reduction of consolidation chemotherapy. Patients aged ⩾60 years reported to the PETHEMA registry and were treated with all-trans retinoic acid (ATRA) plus anthracycline-based regimens according to three consecutive PETHEMA trials that were included. We compared the long-term outcomes of the LPA2005 trial with the preceding PETHEMA trials using non-age-adapted schedules (LPA96&LPA99). From 1996 to 2012, 389 older patients were registered, of whom 268 patients (69%) were eligible. Causes of ineligibility were secondary APL (19%), and unfit for chemotherapy (11%). Median age was 67 years, without relevant differences between LPA2005 and LPA96&LPA99 cohorts. Overall, 216 patients (81%) achieved complete remission with no differences between trials. The 5-year NRM, cumulative incidence of relapse, disease-free survival and overall survival in the LPA2005 vs the LPA96&99 were 5 vs 18% (P=0.15), 7 vs 12% (P=0.23), 87 vs 69% (P=0.04) and 74 vs 60% (P=0.06). A less intensive front-line regimen with ATRA and anthracycline monochemotherapy resulted in improved outcomes in older APL patients.
Palomo L, Malinverni R, Cabezón M, Xicoy B, Arnan M, Coll R, Pomares H, García O, Fuster-Tormo F, Grau J, Feliu E, Solé F, Buschbeck M, Zamora L
DNA methylation profile in chronic myelomonocytic leukemia associates with distinct clinical, biological and genetic features.
Epigenetics2018, 13(1)8-18. Epub 6 Feb 2018
Chromosomal abnormalities are detected in 20-30% of patients with chronic myelomonocytic leukemia (CMML) and correlate with prognosis. On the mutation level, disruptive alterations are particularly frequent in chromatin regulatory genes. However, little is known about the consequential alterations in the epigenetic marking of the genome. Here, we report the analysis of genomic DNA methylation patterns of 64 CMML patients and 10 healthy controls, using a DNA methylation microarray focused on promoter regions. Differential methylation analysis between patients and controls allowed us to identify abnormalities in DNA methylation, including hypermethylation of specific genes and large genome regions with aberrant DNA methylation. Unsupervised hierarchical cluster analysis identified two main clusters that associated with the clinical, biological, and genetic features of patients. Group 1 was enriched in patients with adverse clinical and biological characteristics and poorer overall and progression-free survival. In addition, significant differences in DNA methylation were observed between patients with low risk and intermediate/high risk karyotypes and between TET2 mutant and wild type patients. Taken together, our results demonstrate that altered DNA methylation patterns reflect the CMML disease state and allow to identify patient groups with distinct clinical features.
Palau A, Garz AK, Diesch J, Zwick A, Malinverni R, Valero V, Lappin K, Casquero R, Lennartsson A, Zuber J, Navarro T, Mills KI, Götze KS, Buschbeck M
Polycomb protein RING1A limits hematopoietic differentiation in myelodysplastic syndromes.
Oncotarget29 Dec 2017, 8(70)115002-115017. Epub 1 Dec 2017
Genetic lesions affecting epigenetic regulators are frequent in myelodysplastic syndromes (MDS). Polycomb proteins are key epigenetic regulators of differentiation and stemness that act as two multimeric complexes termed polycomb repressive complexes 1 and 2, PRC1 and PRC2, respectively. While components and regulators of PRC2 such as ASXL1 and EZH2 are frequently mutated in MDS and AML, little is known about the role of PRC1. To analyze the role of PRC1, we have taken a functional approach testing PRC1 components in loss- and gain-of-function experiments that we found overexpressed in advanced MDS patients or dynamically expressed during normal hematopoiesis. This approach allowed us to identify the enzymatically active component RING1A as the key PRC1 component in hematopoietic stem cells and MDS. Specifically, we found that RING1A is expressed in CD34
ABO blood group A transferases catalyze the biosynthesis of FORS blood group FORS1 antigen upon deletion of exon 3 or 4.
Blood Adv26 Dec 2017, 1(27)2756-2766. Epub 20 Dec 2017
Evolutionarily related ABO and GBGT1 genes encode, respectively, A and B glycosyltransferases (AT and BT) and Forssman glycolipid synthase (FS), which catalyze the biosynthesis of A and B, and Forssman (FORS1) oligosaccharide antigens responsible for the ABO and FORS blood group systems. Humans are a Forssman antigen-negative species; however, rare individuals with Apae phenotype express FORS1 on their red blood cells. We previously demonstrated that the replacement of the LeuGlyGly tripeptide sequence at codons 266 to 268 of human AT with GBGT1-encoded FS-specific GlyGlyAla enabled the enzyme to produce FORS1 antigen, although the FS activity was weak. We searched for additional molecular mechanisms that might allow human AT to express FORS1. A variety of derivative expression constructs of human AT were prepared. DNA was transfected into COS1 (B3GALNT1) cells, and cell-surface expression of FORS1 was immunologically monitored. To our surprise, the deletion of exon 3 or 4, but not of exon 2 or 5, of human AT transcripts bestowed moderate FS activity, indicating that the A allele is inherently capable of producing a protein with FS activity. Because RNA splicing is frequently altered in cancer, this mechanism may explain, at least partially, the appearance of FORS1 in human cancer. Furthermore, strong FS activity was attained, in addition to AT and BT activities, by cointroducing 1 of those deletions and the GlyGlyAla substitution, possibly by the synergistic effects of altered intra-Golgi localization/conformation by the former and modified enzyme specificity by the latter.