Clinical implications of measurable residual disease in AML : review of current evidence

Despite the fact that 80% of adult acute myeloid leukaemia patients reach complete morphological remission after induction chemotherapy, many of them relapse. Many studies have shown that detection of minimal residual disease (defined as 'any detectable evidence of persistent leukaemic cells during complete morphological remission') has an added value in prediction of relapse and survival, and is more than just a surrogate marker for already known risk factors in AML. As such, the behaviour of the disease during treatment might become equally or even more important to decide whether or not an upgrade of treatment (such as an allogeneic stem cell transplantation) is necessary to improve outcome. However, there are still many open issues as to what the ideal time point is to measure MRD, which threshold is clinically significant, what sample (peripheral blood or bone marrow) should be used and how we can standardize tests so that results from different labs become comparable. This review gives an overview of currently available evidence regarding technical issues, prognostic impact and MRD-directed treatment in AML

TARP as immunotherapeutic target in AML expressed in the LSC compartment

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NBPF1, a tumor suppressor candidate in neuroblastoma, exerts growth inhibitory effects by inducing a G1 cell cycle arrest

Background: NBPF1 (Neuroblastoma Breakpoint Family, member 1) was originally identified in a neuroblastoma patient on the basis of its disruption by a chromosomal translocation t(1;17)(p36.2;q11.2). Considering this genetic defect and the frequent genomic alterations of the NBPF1 locus in several cancer types, we hypothesized that NBPF1 is a tumor suppressor. Decreased expression of NBPF1 in neuroblastoma cell lines with loss of 1p36 heterozygosity and the marked decrease of anchorage-independent clonal growth of DLD1 colorectal carcinoma cells with induced NBPF1 expression further suggest that NBPF1 functions as tumor suppressor. However, little is known about the mechanisms involved. Methods: Expression of NBPF was analyzed in human skin and human cervix by immunohistochemistry. The effects of NBPF1 on the cell cycle were evaluated by flow cytometry. We investigated by real-time quantitative RT-PCR the expression profile of a panel of genes important in cell cycle regulation. Protein levels of CDKN1A-encoded p21(CIP1/WAF1) were determined by western blotting and the importance of p53 was shown by immunofluorescence and by a loss-offunction approach. LC-MS/MS analysis was used to investigate the proteome of DLD1 colon cancer cells with induced NBPF1 expression. Possible biological interactions between the differentially regulated proteins were investigated with the Ingenuity Pathway Analysis tool. Results: We show that NBPF is expressed in the non-proliferative suprabasal layers of squamous stratified epithelia of human skin and cervix. Forced expression of NBPF1 in HEK293T cells resulted in a G1 cell cycle arrest that was accompanied by upregulation of the cyclin-dependent kinase inhibitor p21(CIP1/WAF1) in a p53-dependent manner. Additionally, forced expression of NBPF1 in two p53-mutant neuroblastoma cell lines also resulted in a G1 cell cycle arrest and CDKN1A upregulation. However, CDKN1A upregulation by NBPF1 was not observed in the DLD1 cells, which demonstrates that NBPF1 exerts cell-specific effects. In addition, proteome analysis of NBPF1-overexpressing DLD1 cells identified 32 differentially expressed proteins, of which several are implicated in carcinogenesis. Conclusions: We demonstrated that NBPF1 exerts different tumor suppressive effects, depending on the cell line analyzed, and provide new clues into the molecular mechanism of the enigmatic NBPF proteins

Whole blood Fe isotopic signature in a sub-Saharan African population

The Fe isotopic composition of an individual's whole blood has recently been shown to be an interesting clinical indicator of Fe status. The present study aimed to evaluate the influence of several endemic characteristics of a representative population of the South Kivu province, an Fe-rich volcanic African region, on the whole blood Fe isotopic composition. Both diabetes mellitus and the ferroportin Q248H mutation are very common in Africa and are strongly associated with impairments in Fe metabolism. Fe isotopic analysis of whole blood samples was carried out using multi-collector inductively coupled plasma-mass spectrometry (after chromatographic isolation of the target element). Forty-two male subjects (between 48 and 59 years old) living in Bukavu (South Kivu) were enrolled in this study. Among the selected population, wild-type subjects and subjects presenting the ferroportin Q248H mutation (heterozygotes and homozygotes) were included. Within each group, diabetic and non-diabetic patients were considered. The whole blood delta Fe-56 value ranged from -3.09% to -2.41%. The delta Fe-56 value shows a significant negative correlation with the ferritin concentration. No correlation could be established between the whole blood delta Fe-56 value and the transferrin concentration, transferrin saturation or serum Fe concentration. The ferroportin Q248H mutation did not seem to have affected the whole blood Fe isotopic signature. The whole blood delta Fe-56 values were significantly higher in diabetic subjects than in non-diabetic subjects and showed a significant negative correlation with body mass index (BMI) values

A Constitutional Translocation t(1;17)(p36.2;q11.2) in a Neuroblastoma Patient Disrupts the Human NBPF1 and ACCN1 Genes

The human 1p36 region is deleted in many different types of tumors, and so it probably harbors one or more tumor suppressor genes. In a Belgian neuroblastoma patient, a constitutional balanced translocation t(1;17)(p36.2;q11.2) may have led to the development of the tumor by disrupting or activating a gene. Here, we report the cloning of both translocation breakpoints and the identification of a novel gene that is disrupted by this translocation. This gene, named NBPF1 for Neuroblastoma BreakPoint Family member 1, belongs to a recently described gene family encoding highly similar proteins, the functions of which are unknown. The translocation truncates NBPF1 and gives rise to two chimeric transcripts of NBPF1 sequences fused to sequences derived from chromosome 17. On chromosome 17, the translocation disrupts one of the isoforms of ACCN1, a potential glioma tumor suppressor gene. Expression of the NBPF family in neuroblastoma cell lines is highly variable, but it is decreased in cell lines that have a deletion of chromosome 1p. More importantly, expression profiling of the NBPF1 gene showed that its expression is significantly lower in cell lines with heterozygous NBPF1 loss than in cell lines with a normal 1p chromosome. Meta-analysis of the expression of NBPF and ACCN1 in neuroblastoma tumors indicates a role for the NBPF genes and for ACCN1 in tumor aggressiveness. Additionally, DLD1 cells with inducible NBPF1 expression showed a marked decrease of clonal growth in a soft agar assay. The disruption of both NBPF1 and ACCN1 genes in this neuroblastoma patient indicates that these genes might suppress development of neuroblastoma and possibly other tumor types

Insertion of an HERV(K) LTR in the intron of NBPF3 is not required for its transcriptional activity

AbstractThe NBPF genes are members of a recently described gene family that has an intricate genomic organization. These genes can be subdivided into two subfamilies based on the presence of an intronic HERV(K) LTR insertion in the 5′ region. A recent report describes a functional implication for this insertion, claiming that only NBPF genes with this insertion are transcriptionally active [Illarionova, A.E., Vinogradova, T.V., Sverdlov, E.D., 2007. Only those genes of the KIAA1245 gene subfamily that contain HERV(K) LTRs in their introns are transcriptionally active. Virology, 358 (1): 39–47]. Here, we show that an NBPF gene lacking this insertion, NBPF3, is expressed in a variety of tissues. Thus the effect of HERV(K) LTR insertion on NBPF gene expression remains unknown