Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty-three patients with acute myelogenous leukemia (AML) have received autologous hematopoietic stem cell transplantation (autoHSCT) in our institute from 1997 to 2005. Among them, 3 patients relapsed, and the other 4 patients (17%) showed cytogenetic abnormalities after the autoHSCT. In these 4 patients with AML1/MTG8 or CBFbeta/MYH11 AML, RT-PCR findings using bone marrow cells were all negative when a cytogenetic abnormality was detected. Myelodysplasia was not detected in the bone marrow and no abnormal findings were seen in the peripheral blood. Cytogenetic abnormalities were detected 12-48 months after AutoHSCT, which disappeared in three patients and decreased in the remaining one patient with a median follow up time of 51 months (30-72 months) after their detection. We present our finding together with a review of the literature on post-autoHSCT cytogenetic abnormalities not related to relapse or secondary leukemia/myelodysplastic syndrome.
 ...
PMID:[Transient chromosomal abnormalities following autologous peripheral blood stem cell transplantation for acute myelogenous leukemia]. 1786 97

Core binding factor acute myeloid leukemia (CBF AML), with t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22) and the associated fusion gene transcripts AML1/ETO or CBFbeta/MYH11, has a favourable clinical prognosis although significant numbers of patients still suffer relapse. We examined the prognostic utility of serial bone marrow minimal residual disease (MRD) monitoring by RQ-PCR in a cohort of patients with CBF AML with long term clinical follow-up. Twenty-nine patients were evaluated with a median follow of 34 months. Twelve relapses occurred at a median of 11 months (range 4 - 17) from diagnosis. RQ-PCR levels at diagnosis, post-induction chemotherapy and post-consolidation were not predictive of outcome. However, a >or=1 log(10) rise at any stage in transcript level relative to the level from a remission bone marrow sample correlated with inferior leukemia free survival (LFS) and imminent morphologic relapse (hazard ratio 8.6). Relapses occurred a median of 60 days (range 45 - 272) after a log(10) rise. A >or=1 log(10) rise in transcript levels strongly predicts subsequent morphologic relapse in CBF AML and therefore defines molecular relapse. Our data support a simple RQ-PCR model for prediction of impending relapse which has the potential for widespread clinical applicability. Prospective identification of high risk patients will enable clinical trials to assess the efficacy of treatment initiated at molecular relapse.
 ...
PMID:A >or=1 log rise in RQ-PCR transcript levels defines molecular relapse in core binding factor acute myeloid leukemia and predicts subsequent morphologic relapse. 1829 29

A great proportion of acute myeloid leukemias (AMLs) display cytogenetic abnormalities including chromosomal aberrations and/or submicroscopic mutations. These abnormalities significantly influence the prognosis of the disease. Hence, a thorough genetic work-up is an essential constituent of standard diagnostic procedures. Core binding factor (CBF) leukemias denote AMLs with chromosomal aberrations disrupting one of the CBF transcription factor genes; the most common examples are translocation t(8;21) and inversion inv(16), which result in the generation of the AML1-ETO and CBFbeta-MYH11 fusion proteins, respectively. However, in murine models, these alterations alone do not suffice to generate full-blown leukemia, but rather, complementary events are required. In fact, a substantial proportion of primary CBF leukemias display additional activating mutations, mostly of the receptor tyrosine kinase (RTK) c-KIT. The awareness of the impact and prognostic relevance of these 'second hits' is increasing with a wider range of mutations tested in clinical trials. Furthermore, novel agents targeting RTKs are emanating rapidly and entering therapeutic regimens. Here, we present a concise review on complementing mutations in CBF leukemias including pathophysiology, mouse models, and clinical implications.
 ...
PMID:Complementing mutations in core binding factor leukemias: from mouse models to clinical applications. 1860 46

Nonrandom gene rearrangements have been demonstrated in leukemic cells at diagnosis. These genetic abnormalities are associated with specific types, clinical characteristics, and prognosis of acute leukemia. Common fusion transcripts in childhood acute lymphoblastic leukemia (ALL) are TEL-AML1, E2A-PBX, MLL-AF4, and BCR-ABL (p190) and in acute nonlymphoblastic leukemia (ANLL) are AML-ETO, PML-RARA, and CBFB-MYH11. Reverse transcription-polymerase chain reaction (RT-PCR) for detection of each individual fusion transcript is impractical and time consuming. The purpose of this study was to develop simple RT-PCR methods to identify common fusion transcripts of newly diagnosed acute leukemia in children. Total RNA was extracted from bone marrow samples of children diagnosed with acute leukemia. Multiplex RT-PCR panel A (ALL) included primers for TEL-AML1, E2A-PBX, MLL-AF4, and BCR-ABL (p190) whereas panel B (ANLL) composed of primers for AML-ETO, PML-RARA, and CBFB-MYH11. Known leukemic cell lines were used to serve as positive controls. Eighty three children diagnosed with ALL (n = 63) and ANLL (n = 20) were included in this study. Fusion transcripts could be identified using multiplex RT-PCR panel A for ALL and panel B for ANLL in 26/83 (31.3%) cases. In ALL samples, we found TEL-AML1 = 16/63 (25.4%), E2A-PBX = 3/63 (4.8%), MLL-AF4 = 1/63 (1.6%), and BCR-ABL = 1/63 (1.6%). Four cases of AML1-ETO (20%) and one PML-RARA (5%) were found in ANLL samples. In conclusion, our simple multiplex RT-PCR for detection of fusion transcripts in childhood acute leukemia was found to be a rapid, accurate, and effective method.
 ...
PMID:Simple multiplex RT-PCR for identifying common fusion transcripts in childhood acute leukemia. 1866 25

MicroRNAs (miRNAs) are postulated to be important regulators in cancers. Here, we report a genome-wide miRNA expression analysis in 52 acute myeloid leukemia (AML) samples with common translocations, including t(8;21)/AML1(RUNX1)-ETO(RUNX1T1), inv(16)/CBFB-MYH11, t(15;17)/PML-RARA, and MLL rearrangements. Distinct miRNA expression patterns were observed for t(15;17), MLL rearrangements, and core-binding factor (CBF) AMLs including both t(8;21) and inv(16) samples. Expression signatures of a minimum of two (i.e., miR-126/126*), three (i.e., miR-224, miR-368, and miR-382), and seven (miR-17-5p and miR-20a, plus the aforementioned five) miRNAs could accurately discriminate CBF, t(15;17), and MLL-rearrangement AMLs, respectively, from each other. We further showed that the elevated expression of miR-126/126* in CBF AMLs was associated with promoter demethylation but not with amplification or mutation of the genomic locus. Our gain- and loss-of-function experiments showed that miR-126/126* inhibited apoptosis and increased the viability of AML cells and enhanced the colony-forming ability of mouse normal bone marrow progenitor cells alone and particularly, in cooperation with AML1-ETO, likely through targeting Polo-like kinase 2 (PLK2), a tumor suppressor. Our results demonstrate that specific alterations in miRNA expression distinguish AMLs with common translocations and imply that the deregulation of specific miRNAs may play a role in the development of leukemia with these associated genetic rearrangements.
 ...
PMID:Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. 1883 81

The core-binding factor (CBF) is a master regulator of developmental and differentiation programs, and CBF alterations are frequently associated with acute leukemia. The role of the CBF member RUNX2 in hematopoiesis is poorly understood. Genetic evidence suggests that deregulation of Runx2 may cause myeloid leukemia in mice expressing the fusion oncogene Cbfb-MYH11. In this study, we show that sustained expression of Runx2 modulates Cbfbeta-smooth muscle myosin heavy chain (SMMHC)-mediated myeloid leukemia development. Expression of Runx2 is high in the hematopoietic stem cell compartment and decreases during myeloid differentiation. Sustained Runx2 expression hinders myeloid progenitor differentiation capacity and represses expression of CBF targets Csf1R, Mpo, Cebpd, the cell cycle inhibitor Cdkn1a, and myeloid markers Cebpa and Gfi1. In addition, full-length Runx2 cooperates with Cbfbeta-SMMHC in leukemia development in transplantation assays. Furthermore, we show that the nuclear matrix-targeting signal and DNA-binding runt-homology domain of Runx2 are essential for its leukemogenic activity. Conversely, Runx2 haplo-insufficiency delays the onset and reduces the incidence of acute myeloid leukemia. Together, these results indicate that Runx2 is expressed in the stem cell compartment, interferes with differentiation and represses CBF targets in the myeloid compartment, and modulates the leukemogenic function of Cbfbeta-SMMHC in mouse leukemia.
 ...
PMID:Runx2 induces acute myeloid leukemia in cooperation with Cbfbeta-SMMHC in mice. 1917 5

We report on a 20-year-old man with acute myeloid leukemia (AML) showing a distinct novel CBFB/MYH11 variant fusion transcript. Initial results of bone marrow, chromosome, and flow cytometric analyses were not in accordance with the diagnosis of acute myelomonocytic leukemia with eosinophilia (AML-M4Eo) or AML with a CBFB/MYH11 rearrangement. However, results from 2 commercially available multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) tests repeatedly showed an unusual PCR product from his bone marrow specimen. Not only does this case show a partial insertion of exon 6 of the CBFB (ENSG00000067955) gene, but it also involves novel breakpoints within both exon 6 of the CBFB gene and exon 28 (previously exon 7) of the MYH11 (ENSG00000133392) gene, which is regarded as a previously non-reported, new type (K-type) of CBFB/MYH11 fusion transcript. In addition, our study result was in agreement with the recent report of Schnittger et al. that rare fusion transcripts of CBFB/MYH11 are correlated with an atypical cytomorphology and other aberrant characteristics. Therefore, multiplex RT-PCR and sequence analysis of these atypical products should be performed to diagnose atypical AML with CBFB/MYH11 rearrangement, to predict prognosis of these patients as well as to elucidate the molecular mechanism.
 ...
PMID:Detection of a novel CBFB/MYH11 variant fusion transcript (K-type) showing partial insertion of exon 6 of CBFB gene using two commercially available multiplex RT-PCR kits. 1921 88

It is known that CBFB-MYH11, the fusion gene generated by inversion of chromosome 16 in human acute myeloid leukemia, is causative for oncogenic transformation. However, the mechanism by which CBFB-MYH11 initiates leukemogenesis is not clear. Previously published reports showed that CBFB-MYH11 dominantly inhibits RUNX1 and CBFB, and such inhibition has been suggested as the mechanism for leukemogenesis. Here we show that Cbfb-MYH11 caused Cbfb/Runx1 repression-independent defects in both primitive and definitive hematopoiesis. During primitive hematopoiesis, Cbfb-MYH11 delayed differentiation characterized by sustained expression of Gata2, Il1rl1, and Csf2rb, a phenotype not found in Cbfb and Runx1 knockout mice. Expression of Cbfb-MYH11 in the bone marrow induced the accumulation of abnormal progenitor-like cells expressing Csf2rb in preleukemic mice. The expression of all 3 genes was detected in most human and murine CBFB-MYH11(+) leukemia samples. Interestingly, Cbfb-MYH11(+) preleukemic progenitors and leukemia-initiating cells did not express Csf2rb, although the majority of leukemia cells in our Cbfb-MYH11 knockin mice were Csf2rb(+). Therefore Csf2rb can be used as a negative selection marker to enrich preleukemic progenitor cells and leukemia-initiating cells from Cbfb-MYH11 mice. These results suggest that Cbfb/Runx1 repression-independent activities contribute to leukemogenesis by Cbfb-MYH11.
 ...
PMID:Cbfb/Runx1 repression-independent blockage of differentiation and accumulation of Csf2rb-expressing cells by Cbfb-MYH11. 2000 44

We hypothesized that DNA methylation distributes into specific patterns in cancer cells, which reflect critical biological differences. We therefore examined the methylation profiles of 344 patients with acute myeloid leukemia (AML). Clustering of these patients by methylation data segregated patients into 16 groups. Five of these groups defined new AML subtypes that shared no other known feature. In addition, DNA methylation profiles segregated patients with CEBPA aberrations from other subtypes of leukemia, defined four epigenetically distinct forms of AML with NPM1 mutations, and showed that established AML1-ETO, CBFb-MYH11, and PML-RARA leukemia entities are associated with specific methylation profiles. We report a 15 gene methylation classifier predictive of overall survival in an independent patient cohort (p < 0.001, adjusted for known covariates).
 ...
PMID:DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. 2012 41

MicroRNAs (miRNAs, miRs) are postulated to be important regulators in various cancers, including leukemia. In a large-scale miRNA expression profiling analysis of 435 human miRNAs in 52 acute myeloid leukemia (AML) samples, we found that miR-126 and its minor counterpart in biogenesis, namely, miR-126*, were specifically aberrantly overexpressed in core binding factor (CBF) AMLs including both t(8;21)/AML1-ETO and inv(16)/CBFB-MYH11 samples. Our in vitro gain- and loss-of-function experiments showed that forced expression of miR-126 inhibited apoptosis and increased the viability of AML cells, whereas the opposite effect was observed when endogenous expression of miR-126 was knocked down. In addition, through in vitro colony-forming/replating assays, we demonstrated that forced expression of miR-126 enhanced proliferation and colony-forming/replating capacity of mouse normal bone marrow progenitor cells alone and particularly, in cooperation with AML1-ETO, a fusion gene resulting from t(8;21). Thus, our data shows that miR-126 may play a critical role in the development of CBF leukemias. In the present chapter, the materials and protocols for the study of miR-126 in leukemia are described.
 ...
PMID:In vitro functional study of miR-126 in leukemia. 2093 98


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>