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Episomes with the NUP214-ABL1 fusion gene have been observed in 6% of T-ALL. In this multicentric study we collected 27 cases of NUP214-ABL1-positive T-ALL. Median age was 15 years with male predominance. Outcome was poor in 12 patients. An associated abnormality involving TLX1 or TLX3 was found in all investigated cases. Fluorescent in situ hybridization revealed a heterogeneous pattern of NUP214-ABL1 amplification. Multiple episomes carrying the fusion were detected in 24 patients. Episomes were observed in a significant number of nuclei in 18 cases, but in only 1–5% of nuclei in 6. In addition, intrachromosomal amplification (small hsr) was identified either as the only change or in association with episomes in four cases and two T-ALL cell lines (PEER and ALL-SIL). One case showed insertion of apparently non-amplified NUP214-ABL1 sequences at 14q12. The amplified sequences were analyzed using array-based CGH.These findings confirm that the NUP214-ABL1 gene requires amplification for oncogenicity; it is part of a multistep process of leukemogenesis; and it can be a late event present only in subpopulations. Data also provide in vivo evidence for a model of episome formation, amplification and optional reintegration into the genome. Implications for the use of kinase inhibitors are discussed.Leukemia (2009) 23, 125–133; doi:10.1038/leu.2008.278; published online 16 October 2008 [ABSTRACT FROM AUTHOR]

Abstract: Apoptosis is considered to be a way of eliminating unwanted cells without causing major inflammation. Nevertheless, several lines of evidence show that apoptotic cell-derived antigens can be strong immunogens. The rabies virus glycoprotein G-ERA is an apoptotic molecule. We tested the ability of G-ERA to potentiate a B cell response against an exogenous antigen (influenza hemagglutinin, HA). We found that co-expression of G-ERA and HA in apoptotic bodies increased both the primary and memory HA-specific immune responses. The immunopotentiation of G-ERA is apoptosis-mediated but not necrosis-mediated. Our data indicate that G-ERA-mediated apoptosis might be useful to improve the immunogenicity of live vaccines. [Copyright &y& Elsevier]

The human AML1 gene (also named CBFA2 or RUNX1), located in the 21q22 chromosomal band, encodes for one of the two subunits forming a heterodimeric transcription factor, the human core binding factor (CBF). AML1 protein contains a highly evolutionary conserved domain of 128 amino acids called runt domain, responsible for both heterodimerization with the β subunit of CBF and for DNA binding. AML1 is normally expressed in all hematopoietic lineages and acts to regulate the expression of various genes specific to hematopoiesis playing a pivotal role in myeloid differentiation. AML1 is one of the genes most frequently deregulated in leukemia through different mechanisms including translocation, mutation and amplification. Translocations lead to the formation of fusion genes encoding for chimerical proteins such as AML1-ETO which induces leukemogenesis. Recently, new mechanisms of AML1 deregulation by point mutations or amplification have been reported. To our knowledge, 51 patients (among 805 studied) with AML1 point mutations have been described. Forty of them have acute myeloid leukemia (AML) most often M0 AML. In this subtype of AML, the frequency of AML1 mutation is significantly higher; 21.5% of patients mutated (34/158). Mutations have also been found with lower frequency in other FAB subtype AML (6 cases), in myeloproliferative disorders (6 cases), in myelodysplastic syndrome (3 cases) and rarely in acute lymphoblastic leukemia (1 case). AML1 gene amplification has been found essentially in childhood ALL (12 cases) and more rarely in myeloid malignancies (4 cases). Here, we reviewed all these cases of AML1 point mutations and amplification and focused on the mechanisms of AML1 deregulation induced by these alterations. [ABSTRACT FROM AUTHOR]

The polymerase chain reaction was used to evaluate minimum residual disease in chronic myelogenous leukaemia (CML) patients after bone-marrow transplantation, by amplification of the transcript of the specific bcr/abl hybrid gene. Strict precautions were taken to avoid contamination. Peripheral blood cells from 22 patients transplanted for haematological malignant disorders were analysed. The results were clearcut for positive controls (patients with CML in relapse) and negative controls (patients with malignant disorders other than CML). In 11 of 12 CML patients in clinical and cytogenetic remission the bcr/abl transcript was detected 3 months to 6 years after transplantation. Thus, it appears that cells expressing the bcr/abl mRNA are not eradicated from the blood of CML patients in complete clinical remission even years after bone-marrow transplantation. [ABSTRACT FROM AUTHOR]

T and B cell human responses to European bat lyssavirus (EBLI) induced by post-exposure rabies vaccination (PM virus vaccine) were evaluated by measuring plasmatic titres of EBLI-specific neutralizing antibodies; specific EBLI-binding antibodies; and proliferation indices of peripheral blood lymphocytes stimulated in vitro with EBLI. These parameters for vaccination efficacy were compared with those obtained with vaccine-related viruses (CVS and ERA) and with a non-vaccine- related virus, Mokola virus, the last implicated in vaccination failures. Twenty-two patients exposed to rabies risk who received a reduced rabies post-exposure vaccination were involved in the study. On day 21, vaccine induced CVS-specific neutralizing antibodies in all patients; but EBLI-specific neutralizing antibodies were induced in only 73% of patients. No vaccinee had Mokola-specific neutralizing antibodies. Patients having EBLI-specific neutralizing antibodies were usually those in whom vaccination induced high titres of CVS-specific neutralizing antibodies. On day 21, peripheral blood lymphocytes of 86% of patients could be restimulated in vitro with vaccine, 43% with EBLI and 45% with Mokola. Patients exhibiting a high vaccine-specific proliferation response more likely developed an EBLI - or a Mokola-specific proliferative response. No correlation was found between T and B cell responses. Rabies vaccination induced neither T nor B cell EBLI -specific responses in 22% of patients. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Prospective Multicentric Molecular Study for Poor Prognosis Fusion Transcripts at Diagnosis in Adult B-Lineage ALL Patients: The LALA 94 Experience" that was published in a previous issue.

Summary:The objective of the study was to assess the long-term outcome and impact of stem cell source in patients with acute myelogenous leukemia (AML) who received ASCT in first complete remission (CR). A total of 101 patients (median age 46 years) were included in the study. Cytogenetic categories distribution was: favorable: 18%, intermediate: 42%, and unfavorable: 7%. More than one induction course was needed for CR in 21% of patients. In all, 78% of patients had received at least one course of high-dose ara-C before autologous stem cell transplantation (ASCT). Bone marrow (n=58) or peripheral blood stem cells (PBSC) (n=43) transplantation was performed at a median of 3.5 months from CR. Hematologic recovery and hospitalization duration were significantly reduced in the PBSC group. No toxic death was recorded in this group. The median follow-up of survivors is 67 months (range: 15-183). The 6-year survival, disease-free survival (DFS), and relapse probabilities are 44%, 38%, and 54%, respectively. The presence of a favorable karyotype and the use of PBSC are independently associated to better survival, and DFS by multivariate analysis. Our results confirm that long-term DFS can be achieved with high-dose chemotherapy and ASCT in patients with AML. They show that use of PBSC is associated to very low mortality rate and acceptable morbidity and contributes to an improvement of autotransplant results.Bone Marrow Transplantation (2004) 33, 177-182. doi:10.1038/sj.bmt.1704326 Published online 24 November 2003 [ABSTRACT FROM AUTHOR]

A letter to the editor is presented that discusses the analyses of TET2 mutations in post-myeloproliferative neoplasm acute myeloid leukemias.