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[Nucleotide sequence of a mutant allele and wild type allele SUP1 and comparison of transcripts of SUP1 and SUP2 genes].

Nucleotide sequences of the yeast recessive suppressor gene SUP1 and one of its mutant alleles (supl-ts36) are compared. One open reading frame is found in the gene able to code 438 amino acid residues. The reading frame is not interrupted by introns. Mutant allele supl-ts36 contains one nucleotide change at position + 101 (T----C) inducing the exchange of leucine on serine in N-terminal part of the polypeptide product. The homology between the structure of SUP1 gene and two groups of proteins is found (1.tRNA-binding or nucleotide-binding proteins; 2. mitochondrial proteins coded by mitochondrial genome). The size of transcript for SUP1 gene is 1600 nucleotides corresponding to the coding region of the gene. For SUP2 gene two stable transcripts are found corresponding to approximately 2500 and approximately 1400 nucleotides. The homology between SUP1 and SUP2 genes is not found. The absence of splicing for both SUP1 and SUP2 genes transcripts is demonstrated in the experiments with RNA2 conditional mutants with impaired splicing.

Alleles↗

PubMed1991

Correlation of M-bcr breakpoint with different chromosomal abnormalities in blast crisis Ph1-positive CML.

The molecular genetics of the Philadelphia (Ph1) chromosome, arising from a reciprocal translocation between chromosomes 9 and 22 and involving the genes abl and bcr, has been well characterized. However, the Ph1 chromosome is usually the sole cytogenetic abnormality during the chronic phase of the disease with additional karyotypic abnormalities arising prior to, or during the onset of the blast or acute phase. We have shown that patients with a breakpoint within the 5' region of the M-bcr of the bcr gene have a different sub-set of chromosomal bands involved in the cytogenetic abnormalities observed during the development of blast crisis than those patients with a 3' breakpoint. This suggests that different mechanisms of progression to blast crisis may be implicated for the subgroups groups of patients.

Blast Crisis↗

PubMed2002

Cytogenetic and molecular genetic aspects of essential thrombocythemia.

Essential thrombocythemia (ET) is a chronic myeloid disorder that is characterized by thrombocytosis, thrombohemorrhagic and vasomotor symptoms, a long median survival, and a low risk of transformation to leukemia. ET can be difficult to distinguish from secondary (reactive) thrombocytosis, and the diagnosis of ET can only be made after the exclusion of other marrow disorders with similar features. Although ET has been assumed to be a clonal process, recent studies have suggested that a substantial number of cases classified as ET may actually not be clonal, and nonclonality may be associated with a lower risk of thrombosis. The lack of a characteristic cytogenetic marker for ET confounds analyses of clonality and offers no insight into disease pathogenesis. There is controversy over the proper classification of thrombocytosis associated with the pathological BCR-ABL gene rearrangement; such cases are not clearly distinguishable from chronic myelogenous leukemia (CML) and should be provisionally classified as CML. New insights are emerging into the role of the megakaryocytopoiesis regulator thrombopoietin (TPO) and its receptor, c-Mpl, in ET and related disorders, but TPO-Mpl dynamics appear to be complex. In some familial thrombocythemic syndromes, mutations in the 5' untranslated region of TPO have recently been described, but these have not yet been observed in sporadic ET. In the future, global analysis of gene expression patterns may help overcome diagnostic dilemmas, refine disease classification, and lead to an improved understanding of the pathogenesis of ET.

Chromosome Aberrations↗

PubMed1988

Expression of cellular protooncogenes in the mouse male germ line: a distinctive 2.4-kilobase pim-1 transcript is expressed in haploid postmeiotic cells.

We report that a 2.4-kilobase (kb) pim-1 transcript is expressed in the germ cells of mouse testis. Analysis of purified populations of spermatogenic cell types indicates that the 2.4-kb transcript is selectively expressed in haploid postmeiotic early spermatids. The evidence for a developmentally regulated expression of pim-1 in haploid spermatids suggests a possible developmental role for this protooncogene product. The 2.4-kb pim-1 transcript present in postmeiotic cells differs in size from the 2.8-kb transcript usually detected in somatic tissues. Similar testis-specific transcripts have been seen for mos and abl genes. These data suggest specificity in transcription or processing of certain genes in haploid male germ cells. We have also analyzed other representative protooncogenes, including examples of protein kinases, the ras family, and the "nuclear" protooncogenes. The results indicate that additional protooncogenes are preferentially expressed in either meiotic pachytene cells or postmeiotic early spermatids. These findings suggest a differential regulation of gene expression in these two developmental stages of germ cells. In particular, analysis of expression of the three members of the ras gene family indicates a distinct temporal differential regulation in the expression of the Harvey, Kirsten, and N-ras genes in these germ cells.

Animals↗

PubMed2004

Mechanisms underlying plant resilience to water deficits: prospects for water-saving agriculture.

Drought is one of the greatest limitations to crop expansion outside the present-day agricultural areas. It will become increasingly important in regions of the globe where, in the past, the problem was negligible, due to the recognized changes in global climate. Today the concern is with improving cultural practices and crop genotypes for drought-prone areas; therefore, understanding the mechanisms behind drought resistance and the efficient use of water by the plants is fundamental for the achievement of those goals. In this paper, the major constraints to carbon assimilation and the metabolic regulations that play a role in plant responses to water deficits, acting in isolation or in conjunction with other stresses, is reviewed. The effects on carbon assimilation include increased resistance to diffusion by stomata and the mesophyll, as well as biochemical and photochemical adjustments. Oxidative stress is critical for crops that experience drought episodes. The role of detoxifying systems in preventing irreversible damage to photosynthetic machinery and of redox molecules as local or systemic signals is revised. Plant capacity to avoid or repair membrane damage during dehydration and rehydration processes is pivotal for the maintenance of membrane integrity, especially for those that embed functional proteins. Among such proteins are water transporters, whose role in the regulation of plant water status and transport of other metabolites is the subject of intense investigation. Long-distance chemical signalling, as an early response to drought, started to be unravelled more than a decade ago. The effects of those signals on carbon assimilation and partitioning of assimilates between reproductive and non-reproductive structures are revised and discussed in the context of novel management techniques. These applications are designed to combine increased crop water-use efficiency with sustained yield and improved quality of the products. Through an understanding of the mechanisms leading to successful adaptation to dehydration and rehydration, it has already been possible to identify key genes able to alter metabolism and increase plant tolerance to drought. An overview of the most important data on this topic, including engineering for osmotic adjustment or protection, water transporters, and C4 traits is presented in this paper. Emphasis is given to the most successful or promising cases of genetic engineering in crops, using functional or regulatory genes. as well as to promising technologies, such as the transfer of transcription factors.

Adaptation, Physiological↗

PubMed1995

BCR-ABL: an anti-apoptosis gene in chronic myelogenous leukemia.

The expression of bcr-abl in chronic myelogenous leukemia leads to a large increase in the generation of mature myeloid cells. The key biochemical alteration in this disease is an increased Abl kinase activity. This up-regulation in activity is mediated through the binding of a portion of the Bcr molecule to the SH2 regulatory domain of the Abl protein. One effect of this alteration is a marked increase in resistance to drug induced cell death by apoptosis. This resistance can be overcome with the use of appropriate antisense oligonucleotides to the bcr-abl gene. The role and contribution of apoptosis to the development of the disease and the prospect of using antisense oligonucleotides as therapeutic agents is discussed.

Animals↗

PubMed2003

Impact of p210(Bcr-Abl) on ultraviolet C wavelength-induced DNA damage and repair.

Recently, it was shown that both Bcr and Bcr-Abl can interact with xeroderma pigmentosum group B (XPB/ERCC3), a protein implicated in DNA repair after UV-induced damage. To further analyze the effect of Bcr-Abl on the DNA damage response, we used cell lines stably transfected with the BCR-ABL gene and their parental counterparts (MBA-1 versus MO7E and Bcr-AblT1 versus 4A2(+)-pZAP) and several assays reflecting DNA repair: the comet assay, a radioimmunoassay for cyclobutane pyrimidine dimers, and clonogenic assays. After exposure to UVC (0.5-5.0 joules m(-2)), the Comet assay demonstrated greater efficiency of DNA repair in the BCR-ABL-positive cells (both MBA-1 and Bcr-AblT1) when compared with their parental counterparts. Furthermore, there was less production of the UV-induced DNA adduct-cyclobutane pyrimidine dimers-as well as a more rapid rate of disappearance of these adducts and greater UV survival (clonogenic assays) in MBA-1 cells as compared with MO7E cells. Apoptosis (annexin V-FITC/propidium iodide staining) was markedly reduced in the BCR-ABL-positive cells. These results indicate that BCR-ABL confers enhanced resistance to UV radiation-induced damage and increased efficiency of DNA repair and that these changes are associated with a protective antiapoptotic effect.

Annexin A5↗

PubMed1991

Antisense RNA therapy for CML--an hypothesis.

CML, a myeloproliferative clonal disorder of myeloid stem cells, is characterized by the consistent presence of a bcr-c-abl fusion gene which is formed as a result of a translocation of the c-abl gene from chromosome 9 to downstream of the bcr gene on chromosome 22 (ph'). Current approaches to the treatment of CML are chemotherapy (conventional or aggressive with immuno-modulators) and bone marrow transplantation (BMT). Neither of the above treatment modalities results in long-term remission or cure. Hence, an alternative approach which aims at correcting the genetic defect should be considered. Taking advantage of the consistent abnormal presence of the bcr-c-abl gene in the treated and untreated CML patients at all stages, a gene therapy at the level of blocking mRNA might be considered. Such an antisense RNA therapy should include removal of patient's bone marrow, administration of the gene for constitutive expression of an antisense RNA for the bcr-c-abl fusion gene into the myeloid stem cells and reinjecting the engineered marrow into the patient. Such an approach, comparable to autologous BMT, will have the advantages of absence of graft rejection and possibility of 100% remission. The possible nature of the gene construct for such an antisense RNA therapy is discussed.

Bone Marrow Transplantation↗

PubMed1995

Detection of M-bcr/abl fusion by fluorescence in situ hybridization (FISH) in a case of Ph negative CML.

A balanced reciprocal translocation, t(6;9)(p21;q34), was identified in a female patient diagnosed with chronic myeloid leukemia (CML). Both homologs of chromosome 22 were of normal length and morphology. Southern blotting revealed a bcr rearrangement with BglII and HindIII. Two signals for the abl probe were demonstrated by fluorescence in situ hybridization (FISH), one on the normal chromosome 9 and the second on a chromosome 22. Thus, molecular rearrangement of bcr resulted from insertion of an abl gene within the bcr region despite absence of a Ph chromosome.

Chromosomes, Human, Pair 6↗

PubMed1995

Chromosomal locations of the genes for the beaded filament proteins CP 115 and CP 47.

We have used the polymerase chain reaction (PCR) to amplify CP 115 and CP 47 encoding sequences from human lens cDNA samples. DNA sequence and northern blot analysis were used to confirm human origin. From the determined cDNA sequences, human-specific oligonucleotides were synthesized and assessed for the ability to amplify human genomic DNA. After empirically selecting a primer pair for each gene able to amplify human genomic DNA, and optimizing PCR conditions for human specificity, we used the PCR to screen a panel of mouse/human somatic cell hybrid DNA samples. Amplification of CP 115 or CP 47 sequences in each of the somatic cell hybrid samples was correlated with the presence/absence of human genomic DNA sequences encoding the respective gene sequences. From our results, we conclude that the gene for human CP 115 resides on chromosome 20 and the gene for human CP 47 on chromosome 3. Further mapping using somatic cell lines carrying derivatives of human chromosome 3 localize the gene for CP 47 to 3q21-25. We propose LIFL-H (Lens Intermediate Filament Like-Heavy) for CP 115 and LIFL-L (Lens Intermediate Filament Like-Light) for CP 47 as the gene symbols for these loci.

Animals↗

PubMed1998

Interaction of abl and raf with IL-7 signaling pathway and transformation of pre-B cells from resistant mice.

After in vivo inoculation with abl/myc- and raf/myc-containing retroviruses, BALB/c mice predominantly develop late stage B cell tumors (plasmacytomas) and less frequently develop earlier B-lineage tumors while DBA/2 mice do not develop B-lineage tumors. We have investigated the in vitro tumorigenic potential of these viruses using cultured normal pre-B cell lymphocytes from both BALB/c and DBA/2 mice. Interestingly, both viruses infect cultured pre-B lymphocytes from both mouse strains. Following infection, IL-7 dependent pre-B cells become independent of normal in vitro growth requirements within 24 h and can rapidly form in vivo pre-B lymphomas in both mouse strains. Mechanisms mediating loss of IL-7 dependence are different depending on whether the raf or abl gene is present in myc-containing viruses. IL-7 JAK-STAT signaling is constitutively active in abl/myc induced pre-B cell tumors. In contrast, IL-7 JAK-STAT signaling is not constitutive in raf/myc induced pre-B cell tumors, demonstrating that subversion of this component of IL-7 signal transduction is not obligatory for pre-B cell transformation or loss of IL-7 dependence.

Animals↗

PubMed2003

Mechanisms of resistance to STI571 in Philadelphia chromosome-associated leukemias.

Philadelphia chromosome-associated leukemias are among the most well-understood human malignancies. The importance of BCR-ABL enzymatic activity in the proliferation of the leukemic clone has been confirmed by the high response rates of these leukemias to the ABL-selective tyrosine kinase inhibitor STI571, even in advanced disease phases, which are characterized by increased genetic heterogeneity. Disease relapse has been observed in a subset of patients who had initially responded to STI571. Evidence suggests that BCR-ABL activity is restored in the majority of these cases of acquired resistance. Molecular studies of resistant leukemia cells isolated from patients have implicated BCR-ABL kinase domain point mutation as the most common mechanism of resistance. Additionally, genomic amplification of the BCR-ABL gene can occasionally be detected. This review will highlight mechanisms of STI571 resistance in clinical samples as well as preclinical models.

Amino Acid Sequence↗

PubMed1998

Molecular monitoring of residual disease in chronic myelogenous leukemia patients after therapy.

The degree of tumor load reduction after therapy, which is determined by the degrees of cytoreduction and cytogenetic response, is an important prognostic factor for patients with chronic myelogenous leukemia (CML). Conventional metaphase analysis is considered to be the "gold standard" for evaluating cytogenetic response. The frequency of cytogenetic analysis can be reduced considerably if patients are monitored by molecular methods, such as quantitative Southern blot, fluorescence in situ hybridization (FISH), quantitative western blot, or competitive reverse transcriptase polymerase chain reaction (RT-PCR). Molecular methods can be performed on peripheral blood specimens and are therefore less invasive than cytogenetic analyses of bone marrow metaphases. Furthermore these techniques are applicable to Ph-negative/BCR-AbL-positive cases. Results obtained by Southern blotting, western blotting, and FISH are readily quantifiable but their sensitivity is not generally superior to that of cytogenetic methods. RT-PCR is by far the most sensitive method. Quantitative RT-PCR analysis is the method of choice for monitoring patients after bone marrow transplantation (BMT). Using competitive PCR in patients after BMT, reappearance and/or rising levels of BCR-ABL transcripts can be detected prior to relapse. All complete cytogenetic responders to interferon-alpha are positive for BCR-ABL transcripts. The level of residual disease spans a range over found orders of magnitude. In both interferon-alpha-treated patients and patients after BMT a good correlation between BCR-ABL transcript numbers per microgram of RNA and cytogenetic results has been found. Variables in the competitive PCR assay may be controlled for by quantification of transcripts of the normal ABL gene as an internal standard. We suggest a stepwise strategy for diagnosis and follow-up of CML patients employing molecular methods.

Blotting, Southern↗

PubMed1993

Retrovirally transduced antisense sequences stably suppress P210BCR-ABL expression and inhibit the proliferation of BCR/ABL-containing cell lines.

There is now strong evidence that the BCR-ABL gene product of the Philadelphia chromosome (P210) plays a crucial role in the pathogenesis of chronic myeloid leukemia (CML). We have previously shown that introduction of antisense oligonucleotides into K562 cells could transiently block the expression of P210 and specifically inhibit cellular growth in culture. In this report, we describe the use of a retroviral vector to introduce selected antisense and sense sequences, first into murine B10 cells, previously rendered interleukin-3 (IL-3) independent by transfection of BCR-ABL sequences, and second into K562 cells. The antisense transcripts generated under the control of MoMLV promoter specifically killed B10 cells in the absence of IL-3 and inhibited P210 expression almost completely. In K562 cells, the antisense sequences led to a dramatic reduction of P210 expression and increased their doubling time by more than twofold. This effect was not reversed by the addition of exogenous IL-3 to the culture medium. Control HeLa or HL60 cells infected with the same constructs did not show any change in proliferation rate, despite abrogation of the normal BCR gene products. Rather unexpectedly, P210 suppression was not lethal in K562 cells, showing that such a cell line does not rely entirely on the expression of P210 for surviving, but depends on it as far as growth properties are concerned. We conclude that this approach can successfully achieve stable suppression of the oncogenic protein P210 and may be used to study further the mechanisms by which P210 is transforming cells. The effect on fresh CML cells in bone marrow cultures remains to be assessed before we can tell whether this technique may be used for selective suppression of leukemic hematopoiesis in vitro.

3T3 Cells↗

PubMed2003

Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin.

Identification of signaling pathways downstream of Abl tyrosine kinase may increase our understanding of the pathogenesis of chronic myelogenous leukemia (CML) and suggest strategies to improve clinical treatment of the disease. By combining the use of a phosphospecific antibody recognizing a substrate motif of serine/threonine kinases with bioinformatics, we found that the translational regulators ribosomal protein S6 and 4E-BP1 are constitutively phosphorylated in CML cells. Experiments with specific inhibitors indicated the phosphorylation is downstream of Bcr-Abl kinase and the mammalian target of rapamycin (mTOR). These results suggest that Bcr-Abl may regulate translation of critical targets in CML cells via mTOR. They also provide a rationale for testing the combination of mTOR inhibitors with the Abl kinase inhibitor imatinib in patients with CML. The mTOR inhibitor rapamycin enhanced imatinib-mediated killing of CML cell lines in vitro, and it overcame imatinib resistance in cells with Bcr-Abl gene amplification.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Selective expansion of normal haemopoietic progenitors from chronic myelogenous leukaemia marrow.

CD34+ and CD34+ DR- cells from the bone marrow (BM) of chronic-phase chronic myelogenous leukaemia (CML) patients at diagnosis were tested for their colony-forming ability in response to early and intermediate-late colony stimulating factors (CSFs). Molecular analysis revealed that 55.6+/-9% SD of CD 34+ DR- colonies, in which actin and ABL mRNA were detectable, expressed the product of the BCR-ABL gene. The percentage and the clonogenic efficiency of CML DR- cells were significantly lower than those of comparable DR- cells from normal donors. However, clonogenic assays using recombinant human CSFs demonstrated a remarkable proliferation of CML cells when stimulated by SCF, IL-11 and IL-3, used as single factors in the presence of erythropoietin (EPO) and was almost entirely due to erythroid progenitors. Conversely, optimal stimulation of CD34 +DR- cells from normal donors required co-incubation with three or more CSFs. Stroma-noncontact long-term cultures were then established in the presence of exogenous CSFs and human irradiated allogeneic stromal layers or the murine stromal cell line M2-10B4, engineered to produce G-CSF and IL-3. In these cultures the combination of SCF and IL-3 induced a 25.4 +/- 5 SD, 40 +/- 6 SD and 20.5 +/- 6 SD fold increase of colony-forming unit cells (CFU-C), at weeks 2, 4 and 5, respectively. At the same time-points the number of primitive long-term culture initiating cells (LTC-IC) showed a 4 +/- 2 SD, 3.3 +/- 1.5 SD and 2.3 +/-1 SD fold increase compared to baseline values. BCR-ABL mRNA analysis of single colonies demonstrated that 27 +/- 9% SD and 7 +/- 3% SD CFU-C at weeks 4 and 5, respectively, expressed the fusion gene, whereas leukaemic LTC-IC disappeared from the culture by week 2. These results suggest that leukaemic CD34+ DR- cells have a different pattern of response to CSFs than normal cells. In addition, we established culture conditions which allow selective expansion of benign haemopoietic cells coexisting with leukaemic progenitors.

Antigens, CD34↗

PubMed1995

Regional localization and developmental expression of the BCR gene in rodent brain.

The BCR gene is implicated in the development of Ph-positive leukemia through its fusion with the nonreceptor tyrosine kinase gene ABL. The normal 160 kDa Bcr protein has several functional domains, and recently one specific role for Bcr was established in the regulation of respiratory burst activity in white blood cells. Bcr expression levels are relatively constant throughout mouse development until adulthood in brain and in hematopoietic tissues, a pattern that is distinctly different from that of the functionally related n-chimerin gene. In the present study, RNA in situ hybridization was used to explore the normal cellular function of Bcr in rodent brain and hematopoietic organs. The data pinpoint the high bcr expression in the brain to the hippocampal pyramidal cell layer and the dentate gyrus, and to the piriform cortex and the olfactory nuclei, reflecting a potentially interesting function for Bcr in these highly specialized brain regions.

Animals↗

PubMed1997

Hypersensitivity of bcr-abl-positive progenitors to hyperthermia in patients with chronic myeloid leukemia.

In this study, we evaluated the effect of hyperthermia on hematopoietic progenitors from six chronic myeloid leukemia (CML) bone marrow (BM) samples at diagnosis and four peripheral blood stem cell (PBSC) samples from CML patients after stem cell mobilisation. CD34-positive cells, isolated from these samples, were incubated for 2 h at 37, 42 or 43 degrees C and were plated in the colony-forming unit granulocyte-macrophage (CFU-GM) and the long-term culture initiating cell (LTCIC) assay. To evaluate purging, individual colonies from these assays were analyzed for the presence of the bcr-abl gene with interphase fluorescence in situ hybridization (FISH) and/or RT-PCR. BM samples showed a significant higher sensitivity both at the CFU-GM and LTCIC level, after treatment at 42 degrees C, as compared to the control BM samples obtained from healthy volunteers. The four BM samples of CML patients with a low leukocyte number at diagnosis harbored a mixture of bcr-abl-negative and positive colonies and an increase in the percentage of bcr-abl-negative colonies was observed in all cases. CML patients with a high leukocyte count at diagnosis, however, showed only bcr-abl-positive progenitors even after hyperthermia. PBSCs showed a significant higher sensitivity at the LTCIC level but not at the CFU-GM level, after treatment at 42 degrees C, as compared to the control PBSC samples obtained from nonhematologic cancer patients. Molecular analysis of individual colonies demonstrated an increase of bcr-abl-negative progenitors after thermic treatment in two out of three samples. When comparing both stem cell sources, PBSCs showed a decreased thermic sensitivity as compared to the BM samples at the CFU-GM level, whereas at the LTCIC level an increased thermic sensitivity was observed, both for the controls and the CML samples. In conclusion, both for BM and PBSCs samples, CML progenitors are more sensitive to hyperthermia than control cells, especially at the LTCIC level. In agreement with these results, an increase of bcr-abl-negative progenitors in six out of seven samples could be demonstrated either at the CFU-GM level, LTCIC level or both. Hyperthermia should be explored further as a possible purging modality in CML.

Adult↗