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At least 973 records · Page 54Linked to original sources
PubMed1993

Ph-positive leukemia: a transgenic mouse model.

The presence of the BCR/ABL chimeric gene is the hallmark of defined types of human leukemia. To increase our knowledge of the oncogenic processes and to develop a model for this type of leukemia we generated a BCR/ABL (P190) transgenic mouse line. Over 95% of mice of this line die of leukemia or leukemia/lymphoma within 35-200 days of age. Karyotypically visible genetic alterations were absent from the early stages of BCR/ABL generated leukemia. A high frequency of aneuploidy was found in advanced leukemia indicating a primary and pivotal role for BCR/ABL in leukemogenesis. Moreover, the data suggest that BCR/ABL has a destabilizing effect on the regulation of the cell cycle. BCR/ABL expression was also found in tissues other than hematopoietic cells. However, this did not result in the development of solid tumors, strongly suggesting that the oncogenicity of BCR/ABL is limited to the hematopoietic lineage.

Animals↗
PubMed1994

Chronic neutrophilic leukemia. A study of four cases.

Chronic neutrophilic leukemia (CNL) is a very rare entity, which has to be included among the chronic myeloid leukemias. Once an underlying cause of neutrophilia is excluded, the diagnosis of CNL is based on exclusion of chronic granulocytic and other types of chronic myeloid leukemias. The classification proposed by Sheperd et al. has proven to be helpful, but it must be completed by cytogenetic analysis and the search for bcr rearrangement by molecular biology methods, in order to confirm the absence of Philadelphia chromosome and of bcr-abl hybrid gene. We report here four cases of CNL, with confirmed absence of bcr rearrangement in two cases. Two patients died, 12 and 8 years after diagnosis, the second one following transformation into myelofibrosis with myeloid metaplasia. The other two died of acute myelogenous leukemia, the first one, 25 years after diagnosis of CNL, following a 3-year phase of acceleration. The last patient presented combined features of CNL and refractory anemia with excess of blasts, and was characterized by both progressive leukocytosis and severe thrombocytopenia; acute transformation into acute myelogenous leukemia occurred 6 months after diagnosis and death 1 month later. Among the 30 cases reported so far, plus the four presented here, combined myelodysplastic features were observed in five cases and transformation into acute myelogenous leukemia in six. Chronic neutrophilic leukemias should be reported regularity, in view of the uncertain and low frequency of this hematological disease.

Aged↗
PubMed1992

Parental origin of chromosomes involved in the translocation t(9;22).

Functionally equivalent genetic maternal can be labelled by an epigenetic marking process and used differentially depending on whether its origin is maternal or paternal. This phenomenon is known as genomic imprinting and is manifested at either the chromosomal or gene level. Genomic imprinting seems to play an important role in cancer predisposition syndromes, and phenotypic consequences are evident in constitutional deletion syndromes and uniparental disomies. Moreover, there seems to be a preferential retention of paternal alleles in sporadic tumours such as Wilms' tumour, rhabdomyosarcoma, osteosarcoma and retinoblastoma. To investigate whether chromosomes involved in acquired abnormalities of haematologic neoplasms show a similar 'parent of origin' bias, we studied the inheritance of the translocated chromosomes 9 and 22 in cases of Philadelphia-chromosome-positive leukaemia, using unique specific chromosome band polymorphisms. Here we show that the translocated chromosome 9 was of paternal origin, whereas the translocated chromosomes 22 were derived exclusively from the maternal copy, in 11 cases with reliable polymorphisms. Our data therefore provide evidence that imprinting phenomena may play an important role in acquired tumour-specific chromosome rearrangements.

Adolescent↗
PubMed1999

bcl2 and v-abl oncogenes cooperate to immortalize murine B cells that secrete antigen specific antibodies.

In this manuscript, a general strategy was designed and used to rapidly test whether any combination(s) of p53, v-abl, bcl2 and ras oncogenes could act cooperatively to immortalize B cells. Here we report that only the combination of v-abl and bcl2 was successful. Splenic B cells from beta galactosidase-immunized mice were stimulated in vitro with lipopolysaccharide and dextran sulphate for 48 h and co-infected with ecotropic A-MuLV (v-abl) and amphotropic pZip-bcl2 (human bcl2) viruses. When inoculated i.p. into naive pristane-primed mice, these B cells generated mesenteric lymphadenopathy, intraperitoneal lymph nodules and ascites in 100% (8/8) of the mice within 36-53 days. The ascites fluid contained 69.5-122 microg/ml IgG and 2.5-13 microg/ml IgM against the immunogen. The ascites cells were passed intraperitoneally up to three times. In all passages, ascites tumors were generated, and the ascites fluid contained beta galactosidase-specific IgG and IgM, indicating that some immunoglobulin secreting B cells had been immortalized. Neither ascites nor tumors were produced when B cells infected with only one of the viruses was injected into the mice. The presence of each oncogene in ascites cells was verified by immunohistochemistry or RT-PCR. This study provides evidence for the cooperativity of an unexpected pair of oncogenes in B cell immortalization.

3T3 Cells↗
PubMed1993

Absence of bcr/abl gene in single hemopoietic progenitors in some patients with chronic myelogenous leukemia.

CD34+DR- and CD34+DR+ cells were isolated from the marrow mononuclear cells of five patients with chronic myelogenous leukemia (CML) carrying the Philadelphia (Ph) chromosome. Analysis of bcr/abl hybrid mRNA in individual colonies from a single cell using reverse transcriptase polymerase chain reaction (RT-PCR) demonstrated the presence or absence of the hybrid mRNA. For patient 1 in the chronic phase of CML, the hybrid mRNA was detected in all colonies derived from CD34+DR+ and CD34+DR- hemopoietic progenitors. In contrast, for patient 2 in the chronic phase of CML, the mRNA was detected in all individual colonies from CD34+DR+ progenitors but not in any from CD34+DR- progenitors. For patient 3 in the chronic phase of CML, the mRNA was detected in all individual colonies from CD34+DR+ but in only some of the colonies from CD34+DR- progenitors. For patients 4 and 5 in the acute crisis of CML, the mRNA was found in a portion of colonies from CD34+DR+ and CD34+DR- progenitors. These results indicated that normal clones can persist in CD34+DR- progenitors in some patients with CML, even when chromosome analysis detects the Ph chromosome in all metaphases of bone marrow cells.

Adult↗
PubMed1993

Detection of the BCR/ABL fusion gene in chronic myeloid leukemia by RNA polymerase chain reaction.

The bcr/abl fusion gene in 20 patients with chronic myeloid leukemia (CML) was detected by RNA polymerase chain reaction, which used mRNA as the starting material to generate cDNA with reverse transcriptase followed by PCR amplification (RNA/PCR). Amplification of a sequence spanning the bcr/abl junction region was achieved by using peripheral blood cells as the source of mRNA from all 20 patients with CML, including 3 cases of Ph (-) CML, and cell line K562 was derived from patients with CML. No amplification was seen when mononuclear cells from 3 normal individuals, 2 patients with lymphoma and cell line HL-60 were used. The presence or absence of bcr exon 3 in the fusion mRNA was determined by the size of the amplified fragments. Of the 20 CML patients, 15 showed only the 165-bp amplified band (indicating retention of bcr exon 3), one showed only the 90-bp amplified band, and 4 showed both 165-bp and 90-bp bands. Both bands were seen more frequently in blast crisis than in remission and chronic phase.

Adolescent↗
PubMed2001

Caveolin-1 is a negative regulator of caveolae-mediated endocytosis to the endoplasmic reticulum.

Caveolae are flask-shaped invaginations at the plasma membrane that constitute a subclass of detergent-resistant membrane domains enriched in cholesterol and sphingolipids and that express caveolin, a caveolar coat protein. Autocrine motility factor receptor (AMF-R) is stably localized to caveolae, and the cholesterol extracting reagent, methyl-beta-cyclodextrin, inhibits its internalization to the endoplasmic reticulum implicating caveolae in this distinct receptor-mediated endocytic pathway. Curiously, the rate of methyl-beta-cyclodextrin-sensitive endocytosis of AMF-R to the endoplasmic reticulum is increased in ras- and abl-transformed NIH-3T3 cells that express significantly reduced levels of caveolin and few caveolae. Overexpression of the dynamin K44A dominant negative mutant via an adenovirus expression system induces caveolar invaginations sensitive to methyl-beta-cyclodextrin extraction in the transformed cells without increasing caveolin expression. Dynamin K44A expression further inhibits AMF-R-mediated endocytosis to the endoplasmic reticulum in untransformed and transformed NIH-3T3 cells. Adenoviral expression of caveolin-1 also induces caveolae in the transformed NIH-3T3 cells and reduces AMF-R-mediated endocytosis to the endoplasmic reticulum to levels observed in untransformed NIH-3T3 cells. Cholesterol-rich detergent-resistant membrane domains or glycolipid rafts therefore invaginate independently of caveolin-1 expression to form endocytosis-competent caveolar vesicles via rapid dynamin-dependent detachment from the plasma membrane. Caveolin-1 stabilizes the plasma membrane association of caveolae and thereby acts as a negative regulator of the caveolae-mediated endocytosis of AMF-R to the endoplasmic reticulum.

3T3 Cells↗
PubMed2005

Fusion of EML1 to ABL1 in T-cell acute lymphoblastic leukemia with cryptic t(9;14)(q34;q32).

The BCR-ABL1 fusion kinase is frequently associated with chronic myeloid leukemia and B-cell acute lymphoblastic leukemia but is rare in T-cell acute lymphoblastic leukemia (T-ALL). We recently identified NUP214-ABL1 as a variant ABL1 fusion gene in 6% of T-ALL patients. Here we describe the identification of another ABL1 fusion, EML1-ABL1, in a T-ALL patient with a cryptic t(9;14)(q34;q32) associated with deletion of CDKN2A (p16) and expression of TLX1 (HOX11). Echinoderm microtubule-associated protein-like 1-Abelson 1 (EML1-ABL1) is a constitutively phosphorylated tyrosine kinase that transforms Ba/F3 cells to growth factor-independent growth through activation of survival and proliferation pathways, including extracellular signal-related kinase 1/2 (Erk1/2), signal transducers and activators of transcription 5 (Stat5), and Lyn kinase. Deletion of the coiled-coil domain of EML1 abrogated the transforming properties of the fusion kinase. EML1-ABL1 and breakpoint cluster region (BCR)-ABL1 were equally sensitive to the tyrosine kinase inhibitor imatinib. These data further demonstrate the involvement of ABL1 fusions in the pathogenesis of T-ALL and identify EML1-ABL1 as a novel therapeutic target of imatinib.

Adolescent↗
PubMed1989

Germ-line transmission of a c-abl mutation produced by targeted gene disruption in ES cells.

A substitution mutation has been introduced into the c-abl locus of murine embryonic stem cells by homologous recombination between exogenously added DNA and the endogenous gene, and these cells have been used to generate chimeric mice. It is shown that the c-abl mutation was transmitted to progeny by several male chimeras. This work demonstrates the feasibility of germ-line transmission of a mutation introduced into a nonselectable autosomal gene by homologous recombination.

Abelson murine leukemia virus↗
PubMed2002

Differential expression and signaling of CBL and CBL-B in BCR/ABL transformed cells.

CBL and the related CBL-B protein are two members of a family of RING finger type ubiquitin E3 ligases that are believed to function as negative regulators of signal transduction in hematopoietic and immune cells. In mice, expression of v-Cbl causes lymphomas, and targeted disruption of either the CBL gene or the CBL-B gene can result in a lymphoproliferative disorder or hypersensitivity of lymphocytes. CBL is one of the most prominent targets of the BCR/ABL tyrosine kinase oncogene. We compared the role of CBL and CBL-B in signal transduction of BCR/ABL using pairs of cell lines before and after expression of BCR/ABL. In contrast to CBL, BCR/ABL was found to rapidly downregulate the expression of CBL-B protein. The decrease in CBL-B protein induced by BCR/ABL was associated with downregulation of CBL-B mRNA. Downregulation and tyrosine phosphorylation of CBL-B required BCR/ABL kinase activity. However, despite their known similarities in structure and function, we found CBL and CBL-B proteins to be involved in distinct signaling complexes. CBL was predominantly in a complex with phosphatidylinositol 3'-kinase and CRKL, while CBL-B was not associated with any significant phosphatidylinositol 3'-kinase activity. A major CBL-B associated protein was identified as mono-ubiquitinated Vav, a nucleotide exchange factor for Rac1. These results demonstrate that BCR/ABL signals differentially through CBL and CBL-B, with downregulation of the CBL-B protein potentially contributing to BCR/ABL-mediated transformation.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Signal transducer and activator of transcription (STAT)5 activation by BCR/ABL is dependent on intact Src homology (SH)3 and SH2 domains of BCR/ABL and is required for leukemogenesis.

Signal transducer and activator of transcription (STAT)5 is constitutively activated in BCR/ ABL-expressing cells, but the mechanisms and functional consequences of such activation are unknown. We show here that BCR/ABL induces phosphorylation and activation of STAT5 by a mechanism that requires the BCR/ABL Src homology (SH)2 domain and the proline-rich binding site of the SH3 domain. Upon expression in 32Dcl3 growth factor-dependent myeloid precursor cells, STAT5 activation-deficient BCR/ABL SH3+SH2 domain mutants functioned as tyrosine kinase and activated Ras, but failed to protect from apoptosis induced by withdrawal of interleukin 3 and/or serum and did not induce leukemia in severe combined immunodeficiency mice. In complementation assays, expression of a dominant-active STAT5B mutant (STAT5B-DAM), but not wild-type STAT5B (STAT5B-WT), in 32Dcl3 cells transfected with STAT5 activation-deficient BCR/ABL SH3+SH2 mutants restored protection from apoptosis, stimulated growth factor-independent cell cycle progression, and rescued the leukemogenic potential in mice. Moreover, expression of a dominant-negative STAT5B mutant (STAT5B-DNM) in 32Dcl3 cells transfected with wild-type BCR/ABL inhibited apoptosis resistance, growth factor-independent proliferation, and the leukemogenic potential of these cells. In retrovirally infected mouse bone marrow cells, expression of STAT5B-DNM inhibited BCR/ABL-dependent transformation. Moreover, STAT5B-DAM, but not STAT5B-WT, markedly enhanced the ability of STAT5 activation-defective BCR/ABL SH3+SH2 mutants to induce growth factor-independent colony formation of primary mouse bone marrow progenitor cells. However, STAT5B-DAM did not rescue the growth factor-independent colony formation of kinase-deficient K1172R BCR/ABL or the triple mutant Y177F+R522L+ Y793F BCR/ABL, both of which also fail to activate STAT5. Together, these data demonstrate that STAT5 activation by BCR/ABL is dependent on signaling from more than one domain and document the important role of STAT5-regulated pathways in BCR/ABL leukemogenesis.

Animals↗
PubMed1999

BCR/ABL- CD34(+)HLA-DR- progenitor cells in early chronic phase, but not in more advanced phases, of chronic myelogenous leukemia are polyclonal.

Chronic myelogenous leukemia (CML) is characterized by the Philadelphia (Ph) translocation and BCR/ABL gene rearrangement which occur in a pluripotent hematopoietic progenitor cell. Ph-negative (Ph-) hematopoiesis can be restored in vivo after treatment with -interferon or intensive chemotherapy, suggesting that normal stem and progenitor cells coexist with the Ph+ clone. We have previously shown that Ph- progenitors are highly enriched in the CD34(+)HLA-DR- fraction from early chronic phase (ECP) CML patients. Previous studies have suggested that the Ph-translocation represents a secondary clonal hit occurring in an already clonally mutated Ph- progenitor or stem cells, leaving the unanswered question whether Ph- CD34(+)HLA-DR- progenitors are normal. To show the clonal nature of Ph- CD34(+)HLA-DR- CML progenitors, we have compared the expression of BCR/ABL mRNA with X-chromosome inactivation patterns (HUMARA) in mononuclear cells and in CD34(+)HLA-DR+ and CD34(+)HLA-DR- progenitors in marrow and blood obtained from 11 female CML patients (8 in chronic phase and 3 in accelerated phase [AP] disease). Steady-state marrow-derived BCR/ABL mRNA-, CD34(+)HLA-DR- progenitors had polyclonal X-chromosome inactivation patterns in 2 of 2 patients. The same polyclonal pattern was found in the progeny of CD34(+)HLA-DR- derived long-term culture-initiating cells. Mobilization with intensive chemotherapy induced a Ph-, BCR/ABL mRNA- and polyclonal state in the CD34(+)HLA-DR- and CD34(+)HLA-DR+ progenitors from 2 ECP patients. In a third ECP patient, polyclonal CD34(+) cells could only be found in the first peripheral blood collection. In contrast to ECP CML, steady-state marrow progenitors in late chronic phase and AP disease were mostly Ph+, BCR/ABL mRNA+, and clonal. Further, in the majority of these patients, a Ph-, polyclonal state could not be restored despite mobilization with intensive chemotherapy. We conclude from these studies that CD34(+)HLA-DR- cells that are Ph- and BCR/ABL mRNA- are polyclonal and therefore benign. This population is suitable for autografting in CML.

Adult↗
PubMed1995

The novel activation of ABL by fusion to an ets-related gene, TEL.

In human leukemia, activation of the ABL proto-oncogene locus on chromosome 9 most commonly occurs as a result of its fusion to the BCR locus on chromosome 22. The resulting chimeric protein displays an elevated tyrosine kinase activity. We have identified a novel activation of ABL which involves a gene located on chromosome 12, designated TEL. Like BCR, TEL is fused in-frame with ABL and produces a fusion protein with an elevated tyrosine kinase activity when assayed in an immune complex. The amino-terminal sequences of TEL encode a helix-loop-helix motif which may mediate dimerization.

Amino Acid Sequence↗
PubMed1997

Inhibition of Grb2 and Crkl proteins results in growth inhibition of Philadelphia chromosome positive leukemic cells.

The Bcr-Abl oncoprotein is necessary for the growth of Philadelphia chromosome positive (Ph+) leukemic cells. The Bcr-Abl protein has been found to bind to SH2/SH3-containing adaptor proteins such as Grb2 and Crkl, and these complexes are believed to activate various signaling pathways. Grb2 and Crkl are important for the Bcr-Abl-mediated transformation of rat fibroblasts and murine hematopoietic cells. We have used liposomes to deliver nuclease-resistant antisense oligonucleotides (oligos) that are specific for the GRB2 or CRKL mRNA to leukemic cells to specifically downregulate Grb2 or Crkl protein expression. We found that by downregulating Grb2 or Crkl protein expression, Grb2 or Crkl antisense oligos could selectively inhibit the growth of Bcr-Abl positive cells, but not that of Bcr-Abl negative cells. Our data, together with other investigators' data, strongly indicate that Grb2 and Crkl are vital for the maintenance of cell growth in Ph+ leukemias.

Adaptor Proteins, Signal Transducing↗
PubMedDate not supplied

Structural and functional characterization of the Leishmania amazonensis ribosomal RNA promoter.

The promoter region of the ribosomal RNA (rRNA) genes of Leishmania amazonensis was characterised and the transcription start point, defined by primer extension, was shown to be a T residue, 1048 nucleotides upstream of the beginning of the 18S sequence. A repetitive element of 60 bp was identified in the intergenic spacer. This element did not show sequence similarity with the region around the transcription start point. Conserved sequences were found in the external transcribed spacer of L. amazonensis, Trypanosoma cruzi and Crithidia fasciculata rRNA genes, 150 nucleotides downstream of the transcription start point. These sequences might be involved in processing events of the rRNA precursor molecule. The general organisation of the gene resembles the pattern observed for the ribosomal cistron in eukaryotic cells. Constructs containing the L. amazonensis promoter region upstream of the chloramphenicol acetyltransferase (cat) gene were able to drive the expression of the reporter gene in transient transfection experiments. CAT expression could be detected even when no trans-splicing acceptor sequence was added to the constructs, although its presence enhanced 5-fold the level of CAT activity. Species-specificity of the RNA polymerase I promoter activity was also demonstrated since constructs containing the L. amazonensis promoter region were unable to drive CAT expression when transfected into the related trypanosomatids, T. cruzi, C. fasciculata and Endotrypanum schaudini.

Animals↗
PubMed2001

Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism.

Cherubism (MIM 118400) is an autosomal dominant inherited syndrome characterized by excessive bone degradation of the upper and lower jaws followed by development of fibrous tissue masses, which causes a characteristic facial swelling. Here we describe seven mutations in the SH3-binding protein SH3BP2 (MIM 602104) on chromosome 4p16.3 that cause cherubism.

Adaptor Proteins, Signal Transducing↗
PubMed1998

The products of the yeast MMS2 and two human homologs (hMMS2 and CROC-1) define a structurally and functionally conserved Ubc-like protein family.

Eukaryotic genes encoding ubiquitin-congugating enzyme (Ubc)-like proteins have been isolated from both human and yeast cells. The CROC-1 gene was isolated by its ability to transactivate c- fos expression in cell culture through a tandem repeat enhancer sequence. The yeast MMS2 gene was cloned by its ability to complement the methyl methanesulfonate sensitivity of the mms2-1 mutant and was later shown to be involved in DNA post-replication repair. We report here the identification of a human MMS2 ( hMMS2 ) cDNA encoding a novel human Ubc-like protein. hMMS2 and CROC-1 share >90% amino acid sequence identity, but their DNA probes hybridize to distinct transcripts. hMMS2 and CROC-1 also share approximately 50% identity and 75% similarity with the entire length of yeast Mms2. Unlike CROC-1 , whose transcript appears to be elevated in all tumor cell lines examined, the hMMS2 transcript is only elevated in some tumor cell lines. Collectively, these results indicate that eukaryotic cells may contain a highly conserved family of Ubc-like proteins that play roles in diverse cellular processes, ranging from DNA repair to signal transduction and cell differentiation. The hMMS2 and CROC-1 genes are able to functionally complement the yeast mms2 defects with regard to sensitivity to DNA damaging agents and spontaneous mutagenesis. Conversely, both MMS2 and hMMS2 were able to transactivate a c- fos - CAT reporter gene in Rat-1 cells in a transient co-transfection assay. We propose that either these proteins function in a common cellular process, such as DNA repair, or they exert their diverse biological roles through a similar biochemical interaction relative to ubiquitination.

Amino Acid Sequence↗
PubMed1999

5S rRNA gene deletions cause an unexpectedly high fitness loss in Escherichia coli.

In Escherichia coli, ribosomal RNAs (16S, 23S and 5S) are co-transcribed in a highly regulated manner from seven genomically dispersed operons. Previous studies on the cellular effects of altered levels of two of these rRNAs (16S and 23S) have been useful in better understanding the regulation of rRNA expression. Furthering these studies, we have investigated the effect of 5S rRNA deficiencies on cell fitness through the sequential deletion of 5S rRNA genes. Our findings indicate that the loss of 5S rDNA from multiple genes decreases cell fitness more rapidly than loss of a similar number of 16S and 23S rRNA genes. These results suggest that the cell's innate ability to up-regulate rRNA operons does not compensate for 5S rRNA deficiencies, as was previously shown for 16S and 23S rRNAs. A plasmid-borne 5S rRNA gene is able to compensate for the deleted 5S rRNA genes.

Escherichia coli↗