Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the involvement of the p53 tumor suppressor gene and RAS family proto-oncogenes in BCR/ABL-negative chronic myeloproliferative disorders (CMPD), including nine cases of myelosclerosis with myeloid metaplasia, four polycythemia vera, 10 essential thrombocythemia, one juvenile chronic myeloid leukemia, and eight BCR/ABL-negative chronic myeloid leukemia. Twenty-five samples were studied in the chronic phase, while seven samples were analyzed in the acute accelerated or blastic phase. The presence of mutations in p53 exons 5-9, as well as in N-, K-, H-Ras exons 1 and 2 (containing codons 12, 13, and 61) was tested by the polymerase chain reaction (PCR) single strand conformation polymorphism technique and by PCR direct sequencing. In addition, restriction analysis was performed to screen for gross rearrangements within the p53 locus. Alterations of the p53 tumor suppressor gene and Ras family proto-oncogenes were detected in 2/7 and 3/7 cases of acute phase BCR/ABL-negative CMPD, respectively, while consistently negative in all the chronic phase samples analyzed. These results suggest that p53 inactivation and/or Ras activation might play a role in acute transformation of BCR/ABL-negative CMPD.
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PMID:Mutations in the P53 and RAS family genes are associated with tumor progression of BCR/ABL negative chronic myeloproliferative disorders. 832 Oct 46

We report two cases of Philadelphia chromosome (Ph)-positive acute leukemia with definite myeloid markers. Ph was the sole chromosomal abnormality at presentation, and neither eosinophilia, basophilia, thrombocytosis nor hepatosplenomegaly was present. In both cases, Ph+ myeloblasts showed positive stain for myeloperoxidase and naphthol ASD chloroacetate esterase, which fulfilled the FAB criteria of acute myelogenous leukemia (AML). Ph+ myeloblasts co-expressed myeloid and B-lymphoid antigens (CD10, CD13, CD19 and CD33). In case 1, myeloblasts rearranged M-BCR, and the expression of M-BCR/ABL chimeric RNA was demonstrated by using the reverse transcription polymerase chain reaction (RT-PCR). They also clonally rearranged IGH. Ph clone disappeared on cytogenetic analysis in remission, and granulocytes in remission did not have rearranged M-BCR. In case 2, morphocytochemically distinct myeloid and lymphoid blast populations were seen. Myeloblasts and lymphoblasts were enriched > 96% as CD19-/CD33+ and CD19+/CD33- populations, respectively. Both of them possessed the identical rearrangement of IGH and M-BCR, indicating a common leukemic progenitor cell origin. Furthermore, m-BCR/ABL was detected in addition to M-BCR/ABL on RT-PCR. Accordingly, both cases were diagnosed as de novo Ph+ acute leukemia rather than as chronic myelogenous leukemia in blastic crisis. Their mixed B-lymphoid/myeloid characteristics strongly suggest that so-called 'Ph+ AML' is derived from Ph+ myeloid/B-lymphoid stem cells.
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PMID:B-lymphoid/myeloid stem cell origin in Ph-positive acute leukemia with myeloid markers. 832 35

The very rapid development in the last few years of techniques based on use of the polymerase chain reaction (PCR) for characterizing molecular lesions in leukaemia and lymphoma now offers the opportunity for monitoring residual disease at a sensitivity of one malignant cell in 10(5) or 10(6) normal cells. Maximal specificity is presumably achieved when the DNA sequences amplified are truly leukaemia-specific, such as BCR/ABL in chronic myelogenous leukemia, RARA PML/RARA in t(15;17) acute myelogenous leukemia, DEK/CAN in t(6;9) AML, PBX1/E2A in t(1;19) acute lymphoblastic leukemia (ALL), or TAL-1 deletions in other T-ALLs. Comparable sensitivity may be achieved by using immunoglobulin heavy chain (IGH) and T-cell receptor (TCR) gene rearrangements if a clonospecific probe can be generated. However, the presence of similar sequences in IgH genes from normal B lymphocytes may decrease the specificity. For clinical purposes the crucial issues are the following. Can PCR techniques be used for confirmation of diagnosis and evaluation of extent of disease? Can PCR data obtained in remission provide information about the probability of cure or of relapse? Can techniques be developed to quantitate the PCR product and thereby increase its predictive value? These and other issues were addressed at the 4th Workshop of the Molecular Biology/BMT Study Group that took place in Bristol UK on 9-10 May 1992.
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PMID:Molecular evidence of minimal residual disease after treatment for leukaemia and lymphoma: an updated meeting report and review. 835 Jun 33

An 8 year old girl with adult type Philadelphia (Ph1)-positive chronic myelogenous leukemia received natural alpha-interferon therapy in the chronic phase. Complete suppression of the Ph1 clone of bone marrow cells was achieved after 1 month of therapy, which was determined by disappearance of rearranged breakpoint cluster region (BCR) gene in Southern blot analysis. Complete hematological remission was also attained following 2 months of therapy. Both the suppression and the hematological remission have been sustained for 24 months with alpha-interferon, in spite of the detection of the chimeric BCR/ABL mRNA in her bone marrow by polymerase chain reaction assay 12 months after therapy.
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PMID:A long-term suppression by alpha-interferon of Philadelphia chromosome in children with chronic myelogenous leukemia. 837 32

We report a case of Ph-positive CML where the BM was incubated for 24 h with 10(3) IU/ml IFN gamma and then cultured in liquid media for 4 weeks. After 24 h incubation, there was no differential sensitivity of CML CFU-GM to IFN gamma compared with untreated BM. Subsequent long-term culture (LTC) of the IFN gamma treated CML BM, however, demonstrated a 75% inhibition of production of CFU-GM from the second week onwards. Using PCR, we were able to demonstrate two types of BCR-ABL transcript in the diagnostic BM. After 4 weeks of LTC, the J(bcr b3/ABL II) RNA transcript persisted in the untreated BM, whereas neither BCR/ABL RNA transcripts were detected in the culture established with IFN gamma-treated CML BM. This study has two points of interest with the demonstration of (1) a possible antileukaemic effect of IFN gamma on the progenitors generated in the LTC system, and (2) the use of highly sensitive PCR technology to evaluate the effectiveness of IFN gamma to purge CML BM of Ph-positive cells.
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PMID:Interferon gamma is effective for BM purging in a patient with CML. 840 63

Chronic myelogenous leukemia (CML) is characterized by a specific chromosomal translocation occurring between the long arms of chromosomes 9 and 22 resulting in a fusion product, p210 BCR/ABL, which has elevated tyrosine kinase activity. Expression of p210 BCR/ABL in murine interleukin-3 (IL-3)--dependent cell lines typically converts these cell lines to factor-independence by a non-autocrine mechanism. The IL-3 receptor is believed to function in part by activating a receptor-associated tyrosine kinase, leading to the hypothesis that p210 BCR/ABL may induce factor-independence of myeloid cells by constitutively phosphorylating some common signal-transducing proteins that normally would be phosphorylated on tyrosine residues in response to IL-3. p210 BCR/ABL subclones were constructed from an IL-3-dependent murine myeloid cell line, 32Dcl3, by transfection of a plasmid containing a full-length p210 BCR/ABL cDNA. Following transfection, the cells became completely factor-independent within 3 weeks. We examined the effects of p210 BCR/ABL and IL-3 on the pattern of tyrosine phosphorylation of cellular proteins in 32Dcl3 cells using one- and two-dimensional antiphosphotyrosine immunoblotting. WEHI-3B conditioned media (WEHI-CM) was used as a source of IL-3. The introduction of p210 BCR/ABL results in constitutively increased levels of tyrosine phosphorylation of more than 20 new proteins, while WEHI-CM induced transient tyrosine phosphorylation of 6 to 10 new proteins. Using two-dimensional immunoblots to examine phosphoproteins, four categories could be identified: (1) proteins that are inducibly tyrosine phosphorylated in response to WEHI-CM in 32Dcl3 cells only, (2) proteins inducibly tyrosine phosphorylated by WEHI-CM only in p210 BCR/ABL+ cells, (3) proteins that are inducibly tyrosine phosphorylated in response to WEHI-CM in both 32Dcl3 cells and p210 BCR/ABL+ cells, and (4) proteins inducibly tyrosine phosphorylated in response to WEHI-CM and constitutively phosphorylated in the presence of p210 BCR/ABL. We have identified one of the proteins in category 4 as p42 mitogen-activated protein (MAP) kinase (ERK2). Overall, however, we found that the signal transduction pathways of IL-3 and BCR/ABL are strikingly different, suggesting that most of the immediate substrates of the IL-3 receptor-activated tyrosine kinase and p210 BCR/ABL kinase are different. Convergence of signaling pathways at p42 MAP kinase is of interest since activation of this kinase has been linked to mitogenesis in many systems. Identification of the overlapping proteins of both IL-3 signal transduction in 32Dcl3 cells and p210 BCR/ABL+ cells may help explain the growth-promoting effects of this oncogene.
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PMID:Interleukin-3 and p210 BCR/ABL activate both unique and overlapping pathways of signal transduction in a factor-dependent myeloid cell line. 840 19

P210 BCR/ABL is a chimeric oncogene implicated in the pathogenesis of chronic myelogenous leukemia. BCR sequences have been shown to be required for activation of the tyrosine kinase and transforming functions of BCR/ABL. In this work, we show that two other structural requirements for full transforming activity of P210 BCR/ABL include a functional tyrosine kinase and the presence of tyrosine 1294, a site of autophosphorylation within the tyrosine kinase domain. Replacement of tyrosine 1294 with phenylalanine (1294F) greatly diminishes the transforming activity of BCR/ABL without affecting the specific activity of the protein tyrosine kinase. Expression of an exogenous myc gene in fibroblasts partially complements the transforming capacity of mutant P210 BCR/ABL (1294F). Surprisingly, tyrosine 1294 is not required for efficient induction of growth factor-independence in hematopoietic cell lines by P210 BCR/ABL. These results suggest that autophosphorylation at tyrosine 1294 may be important for recognition and phosphorylation of cellular substrates in the pathway of transformation, but it is not critical for mediating the events which lead to growth factor independence.
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PMID:SH1 domain autophosphorylation of P210 BCR/ABL is required for transformation but not growth factor independence. 844 9

There is remarkable recent progress in our understanding of the biology of chronic myelogenous leukemia (CML). First, the BCR/ABL rearrangement was identified as the molecular basis of the disease. Second, animal models support the notion that the BCR/ABL gene product causes a syndrome similar to CML. Third, recent advances in understanding the functions of the normal ABL protein have given clues to the mechanism(s) of ABL-induced leukemias and approaches to blocking this process. Extrapolating these findings to humans seems reasonable. The challenge now is to determine how the BCR/ABL gene product causes chronic phase CML. Also unresolved is whether BCR/ABL also plays a role in the acute phase of the disease. Finally, the relationship between the two common forms of BCR/ABL, the P190 and P210 configurations, and different disease phenotypes, like CML and Philadelphia (Ph1)-chromosome positive acute lymphoblastic leukemia (ALL), needs to be clarified. There is also substantial progress in treating CML. Bone marrow transplants have emerged as the preferred therapy. These result in long-term leukemia-free survival in more than one-half of appropriately selected subjects. How transplants cure CML is complex and controversial. Some data suggest high-dose treatment is the dominant factor whereas other data implicate antileukemia effects of the immune system. Interferon treatment has also proven effective in CML. Whether it prolongs survival of persons with CML remains to be determined, as does its mechanism of action. Certainly the most important and difficult challenge in CML therapy is determining how to use knowledge about the causes CML to treat the disease. These and other issues in the biology and therapy of CML were the subject of a recent meeting of basic and clinical scientists. The meeting, third in a series begun in 1987, was held on Martha's Vineyard, Cape Cod, Massachusetts, USA from 4-7 April, 1992. Four major topics were considered in five sessions: molecular biology, cell biology, Ph1-chromosome positive ALL, and therapy of CML. This report summarizes meeting highlights.
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PMID:Chronic myelogenous leukemia: biology and therapy. 846 45

Mice reconstituted with BCR/ABL-infected 5-fluorouracil-treated bone marrow are considered a model system for human chronic myelogenous leukemia, a malignancy that arises in hematopoietic stem cells. These animals develop multiple types of hematopoietic tumors, which could arise either from undifferentiated cells that mature during tumor development or from progenitors committed to different lineages. To examine the BCR/ABL-sensitive target cells present in the marrow of mice treated with 5-fluorouracil, we used a single-step in vitro assay. These experiments revealed that both the P210 and P185 BCR/ABL proteins and the related v-abl protein induce lymphoid and myeloid colonies, colony types that mimic two of the prominent types of tumors found in the reconstitution model. The lymphoid colonies were similar to lymphoid colonies found following infection of normal bone marrow with respect to differentiation state and tumorigenicity. The cells in the myeloid colonies were differentiated and non-tumorigenic. Fluorescence-activated cell sorting revealed that most of the lymphoid and myeloid colonies arose from distinct precursors and that the lymphoid colonies arose from B-lineage-committed cells. These data suggest that most of the lymphomas observed in the reconstitution model arise from committed progenitors that are distinct from those involved in the myeloid disease.
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PMID:ABL oncogenes directly stimulate two distinct target cells in bone marrow from 5-fluorouracil-treated mice. 847 46

To evaluate the remission quality of Philadelphia chromosome (Ph)-positive, BCR/ABL-positive CML patients after allogeneic bone marrow transplantation (BMT) we used the polymerase chain reaction (PCR) to detect BCR-ABL specific RNA in addition to Southern blotting, cytogenetic, and hematological investigation. Fifty-five bone marrow samples of 27 patients in clinical remission were studied by PCR, 0.5 to 99 months (median 8 months) after BMT. The median clinical follow-up of this cohort of patients is 24 months (1-109) after BMT. BCR-ABL transcripts could be detected in 16 out of 27 patients (59%). Risk factors for minimal residual leukemia (MRD) as defined by PCR were the kind of graft-versus-host disease (GvHD) prophylaxis (patients with T-cell-depleted grafts had a higher rate of MRD in comparison to patients treated with methotrexate/cyclosporin A) and the presence or absence of GvHD after BMT (patients without GvHD had a higher incidence of MRD than patients with GvHD). Moreover, the detection of minimal residual leukemia had prognostic significance. Out of 16 patients with minimal residual leukemia as detected by PCR, four patients relapsed clinically and two further cases relapsed cytogenetically. In contrast none of the patients lacking evidence of minimal residual leukemia relapsed. Serial PCR analysis may prove helpful in deciding about further therapeutic interventions (e.g. interferon therapy or adoptive immunotherapy) before leukaemic relapse becomes manifest after BMT.
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PMID:Influence of graft-versus-host disease on the eradication of minimal residual leukemia detected by polymerase chain reaction in chronic myeloid leukemia patients after bone marrow transplantation. 848 29


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