Drug resistance associated properties of blasts subpopulations with different CD34 expression in childhood acute lymphoblastic leukemia (ALL)

Aim: The objective of this study was to investigate expression of drug resistance associated genes in CD34+ and CD34- leukemic subpopulations in childhood acute lymphoblastic leukemia (ALL). Methods: ALL samples with heterogeneous CD34 expression were separated into CD34-positive and CD34-negative subpopulations and mRNA levels of MDR1, LRP , BCRP and BCL-2 genes were compared. Results: BCL-2 gene expression levels did not differ significantly between CD34+ vs CD34− subpopulations in most analyzed ALL cases. Oppositely, MDR1 gene had >two-fold differences in expression levels between subpopulations in the majority of ALL cases. In T-lineage ALL CD34− fractions had increased level of BCRP and LRP genes in comparison with CD34+ ones whereas in most of B-lineage ALL expression of these genes did not differ. Conclusion: It was not found the unique pattern of resistance related genes expression in CD34+ vs CD34− subpopulations. However, in majority of studied pediatric ALL cases with CD34 heterogeneous expression one of subpopulations (positive or negative) could have an advantage for survival through elevated expression of drug resistance related genes

Hematopoietic stem cell transplantation for Wiskott-Aldrich syndrome: an EBMT Inborn Errors Working Party analysis

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients affected by Wiskott-Aldrich syndrome (WAS). Reported HSCT outcomes have improved over time with respect to overall survival, but some studies have identified older age and HSCT from alternative donors as risk factors predicting poorer outcome. We analyzed 197 patients undergoing transplant at European Society for Blood and Marrow Transplantation centers between 2006 and 2017 who received conditioning as recommended by the Inborn Errors Working Party (IEWP): either busulfan (n = 103) or treosulfan (n = 94) combined with fludarabine 6 thiotepa. After a median follow-up post-HSCT of 44.9 months, 176 patients were alive, resulting in a 3-year overall survival of 88.7% and chronic graft-versus-host disease (GVHD)-free survival (events include death, graft failure, and severe chronic GVHD) of 81.7%. Overall survival and chronic GVHD-free survival were not significantly affected by conditioning regimen (busulfan-vs treosulfan-based), donor type (matched sibling donor/matched family donor vs matched unrelated donor/mismatched unrelated donor vs mismatched family donor), or period of HSCT (2006-2013 vs 2014-2017). Patients aged = 5 years remains a risk factor for overall survival.Transplantation and immunomodulatio

Clinical observation of a combination of diffuse alveolar-septal pulmonary lesion and amyloid cardiomyopathy in systemic AL-amyloidosis in the elderly [Клиническое наблюдение сочетания диффузного альвеолярно-септального варианта поражения легких и амилоидной кардиомиопатии при системном AL-амилоидозе в пожилом возрасте]

A rare observation of systemic AL-amyloidosis with a debut in old age, accompanied by diffuse alveolar-septal lesion of the lungs and me-diastinal lymphadenopathy in combination with amyloid cardiomyopathy in the absence of pathology of kidney and liver function. © 2018 Media Sphera Publishing Group. All rights reserved

The Clinical and Genetic Spectrum of 82 Patients WithRAGDeficiency Including a c.256_257delAA Founder Variant in Slavic Countries

Background:Variants in recombination-activating genes (RAG) are common genetic causes of autosomal recessive forms of combined immunodeficiencies (CID) ranging from severe combined immunodeficiency (SCID), Omenn syndrome (OS), leaky SCID, and CID with granulomas and/or autoimmunity (CID-G/AI), and even milder presentation with antibody deficiency. Objective:We aim to estimate the incidence, clinical presentation, genetic variability, and treatment outcome with geographic distribution of patients with theRAGdefects in populations inhabiting South, West, and East Slavic countries. Methods:Demographic, clinical, and laboratory data were collected fromRAG-deficient patients of Slavic origin via chart review, retrospectively. Recombinase activity was determinedin vitroby flow cytometry-based assay. Results:Based on the clinical and immunologic phenotype, our cohort of 82 patients from 68 families represented a wide spectrum ofRAGdeficiencies, including SCID (n= 20), OS (n= 37), and LS/CID (n= 25) phenotypes. Sixty-seven (81.7%) patients carriedRAG1and 15 patients (18.3%) carriedRAG2biallelic variants. We estimate that the minimal annual incidence ofRAGdeficiency in Slavic countries varies between 1 in 180,000 and 1 in 300,000 live births, and it may vary secondary to health care disparities in these regions. In our cohort, 70% (n= 47) of patients withRAG1variants carried p.K86Vfs*33 (c.256_257delAA) allele, either in homozygous (n= 18, 27%) or in compound heterozygous (n= 29, 43%) form. The majority (77%) of patients with homozygousRAG1p.K86Vfs*33 variant originated from Vistula watershed area in Central and Eastern Poland, and compound heterozygote cases were distributed among all Slavic countries except Bulgaria. Clinical and immunological presentation of homozygousRAG1p.K86Vfs*33 cases was highly diverse (SCID, OS, and AS/CID) suggestive of strong influence of additional genetic and/or epigenetic factors in shaping the final phenotype. Conclusion:We propose thatRAG1p.K86Vfs*33 is a founder variant originating from the Vistula watershed region in Poland, which may explain a high proportion of homozygous cases from Central and Eastern Poland and the presence of the variant in all Slavs. Our studies in this cohort ofRAG1founder variants confirm that clinical and immunological phenotypes only partially depend on the underlying genetic defect. As access to HSCT is improving among RAG-deficient patients in Eastern Europe, we anticipate improvements in survival.Transplantation and immunomodulatio