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

The c-myb protooncogene encodes proteins that are critical for hematopoietic cell proliferation and development. Disrupting c-myb function might, therefore, prove an effective therapeutic strategy for controlling leukemic cell growth. Antisense oligodeoxynucleotides have been utilized for this purpose in vitro, but their in vivo efficacy has not been reported. We therefore established human leukemia-scid mouse chimeras with K562 cells and treated diseased animals with phosphorothioate-modified antisense oligodeoxynucleotides. K562 cells express the c-myb protooncogene, which served as the target for the antisense DNA. They also express the tumor-specific bcr-abl oncogene that was utilized to track the human cells in the mouse host. Once circulating leukemic blast cells had been detected, the survival of untreated control mice was 6 +/- 3 days (mean +/- SD). The survival of animals treated for 7 or 14 days with either sense or scrambled-sequence c-myb oligodeoxynucleotides was not statistically different from the control animals. In distinct contrast, animals treated for similar lengths of time with antisense c-myb oligodeoxynucleotides survived at least 3.5 times longer than the various control animals. In addition, animals receiving antisense c-myb DNA had significantly less disease at the two sites most frequently manifesting leukemic cell infiltration, the central nervous system and the ovary. These results suggest that phosphorothioate-modified antisense DNA may be efficacious for the treatment of human leukemia in vivo, and by analogy, for the treatment of other human neoplasias.
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PMID:In vivo treatment of human leukemia in a scid mouse model with c-myb antisense oligodeoxynucleotides. 128 45

Chronic myelogenous leukaemia is a clonal neoplasm of the pluripotent haematopoietic stem cell which is characterized in most patients by a consistent cytogenetic abnormality known as the Philadelphia chromosome. This chromosome occurs as a consequence of a reciprocal translocation between the long arms of chromosomes 9 and 22 which results in the creation of a new gene comprising sequences from the c-abl gene on chromosome 9 and the bcr gene on chromosome 22. The protein encoded by this structurally altered hybrid gene differs from the normal c-abl gene product in both molecular weight and in tyrosine kinase activity. It is likely that these alterations in the c-abl gene product play a central role in the pathogenesis of this leukaemia.
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PMID:Molecular pathogenesis of chronic myelogenous leukaemia. 130 82

The polymerase chain reaction (PCR) cannot be used to amplify the breakpoint in the chimaeric BCR-ABL gene in CML and acute leukaemias due to the large variation in the sites of breakpoint in the BCR gene (within a 5.8 kb region) and in the ABL gene (within a 150 kb region). The disease state is usually monitored using RNA-PCR to monitor abnormal transcripts. We have used a new modification of the PCR to amplify breakpoints within zone 3 of the M-bcr. A synthetic oligonucleotide linker, the Vectorette, is ligated to restriction digested DNA, and amplification is carried out between primers for a known target sequence and the Vectorette linker. Three Philadelphia chromosome Ph1-positive CML patients with breakpoints within the ALU region of zone 3 have been amplified and the sequence immediately around the breakpoint determined. The breaks occurred within 70 bp and two were only 14 bp apart. The Vectorette-PCR technique has the potential to rapidly identify and sequence breakpoints, and will enable the design of patient-specific primers to monitor disease progression, particularly following bone marrow transplantation.
Leukemia 1992 May
PMID:Amplification and sequencing of genomic breakpoints located within the M-bcr region by Vectorette-mediated polymerase chain reaction. 131 90

Philadelphia chromosome (Ph') was detected at presentation in 10 out of 110 patients with acute lymphoblastic leukemia (ALL) and five of 168 patients with acute myelogenous leukemia (AML). Two other ALL patients who had studies at relapse were also included in the analyses. One of the 12 Ph'-positive (Ph+) ALL patients had simultaneous expression of myeloid-associated antigen on the leukemic blasts, while all the five AML patients coexpressed markers of lymphoid cells. Double labeling of the cells with myeloperoxidase and CD10 on three Ph+ AML cases showed that most leukemic blasts expressed either myeloperoxidase activity or CD10 but not both. Cross-lineage gene rearrangements of T-cell receptor (TCR) beta-chain gene were detected in three of the eight Ph+ ALL patients tested. All the four Ph+ AML cases studied showed immunoglobulin heavy chain gene rearrangements, and three of them also had simultaneous rearrangements of TCR beta-chain gene. The results revealed that Ph+ acute leukemia in this study belonged either to ALL or mixed lineage leukemia, and none was pure AML. This finding is contrary to that of acute blast crisis of chronic myelogenous leukemia in which the majority of patients had myeloid transformation. Rearrangements of bcr were detected in four of the 10 Ph+ ALL and three of the four Ph+ AML patients tested. No significant difference was noted in the clinical or hematologic manifestations among Ph+ leukemia with or without bcr rearrangements.
Leukemia 1992 Sep
PMID:Characterization of Philadelphia-chromosome-positive acute leukemia by clinical, immunocytochemical, and gene analysis. 132 82

The nucleoside analog acyclovir (9-[2-hydroxy-ethoxy)methyl]guanine or acycloguanosine; ACV) inhibited the in vitro transformation of NIH 3T3 cells by Abelson murine leukemia virus and the proliferation of abl- and bcr-abl-transformed hemopoietic murine cell lines. This effect is selective since ACV at the same concentration had no effect on the src and Ha-ras transformation of NIH 3T3 cells or on the proliferation of hemopoietic cells transformed by those oncogenes. The inhibitory effect on proliferation of abl-transformed cells correlated with the extent of ACV triphosphate formation and incorporation into cellular DNA that was greater than that in normal or other oncogene-transformed cells. The increased ACV triphosphate formation might be due to a higher level of 5'-nucleotidase, the enzyme responsible for trace levels of ACV phosphorylation in uninfected cells.
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PMID:Selective inhibition of proliferation in v-abl- and bcr-abl-transformed cells by a nucleoside analog. 133 Oct 46

It has been shown that a 600 bp long cluster of cell lineage specific hypomethylated sites in the major breakpoint cluster region (M-bcr) on chromosome 22 exists in hematopoietic cells. To determine possible relationships between methylation patterns within the M-bcr and the stage of hematopoietic cell development, the M-bcr methylation status of 39 patients with leukemia and lymphoma and two patients with myelodysplastic syndrome with non-rearranged M-bcrs was examined by BgIII-HpaII digestion. In the myeloid malignancies, the presence of a hypermethylated 4.8 kb BgIII-BgIII M-bcr allele was directly proportional to the combined myeloblast and promyelocyte percentage of the specimen, whereas the presence of a 2.5 kb BgIII-HpaII allele was directly proportional to the combined percentage of monocytic cells and neutrophils. All five acute monoblastic leukemias showed a methylation pattern that closely resembled neutrophils. All of thirteen surface immunoglobulin positive B-cell malignancies showed a distinct methylation pattern consisting of three or more BgIII-HpaII restriction fragments of 2.5 kb or less in length. The B-cell precursor leukemias showed heterogeneous M-bcr methylation patterns, with four of seven showing a B-cell pattern and three showing a hypermethylated pattern with 4.8, 3.1/3.0 and/or 2.5 kb BgIII-HpaII M-bcr alleles. It is concluded that the M-bcr methylation status is related to the maturation of the neutrophil series; the surface immunoglobulin positive B-cell malignancies are characterized by a distinct, extreme hypomethylation pattern of the M-bcr; and the B-cell precursor malignancies appear to have a heterogeneous M-bcr methylation pattern.
Leukemia 1992 Jan
PMID:Methylation status of the major breakpoint cluster region in Philadelphia chromosome negative leukemias. 134 43

We describe here a patient with accelerated phase Philadelphia chromosome (Ph1) negative chronic myelogenous leukemia without BCR gene rearrangement, who received an allogeneic bone marrow transplant following a conditioning regimen consisting of busulfan (BU) and cyclophosphamide (CY). Hematopoiesis was restored following splenectomy performed 1 month post-transplant. There were no distinguishing cytogenetic differences between donor and host. Five years post-transplant the patient relapsed with the original disease. Restriction fragment length polymorphism (RFLP) studies performed at that time exhibited host specific DNA markers suggesting recurrent leukemia of host origin. RFLP analysis of the cells cryopreserved immediately post-transplant also revealed all cells to be of host origin. This patient experienced 5 years of remission with autologous hematopoietic recovery from an aggressive myeloproliferative disorder after high dose BU and CY without engraftment of donor hematopoietic cells.
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PMID:Prolonged remission of accelerated phase Philadelphia chromosome negative chronic myeloid leukemia following autologous recovery of normal hematopoietic elements after busulfan/cyclophosphamide and allogeneic marrow transplantation. 134 49

The involvement of the BCRlABL fusion gene in patients with Philadelphia (Ph) chromosome positive chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL) is well characterised, but the molecular events underlying the cases of Ph-negative CML and ALL that lack BCR gene involvement and those that cause transformation of Ph-positive CML are unknown. The murine ABL gene can be activated by genetic events that do not involve the BCR gene, including the introduction of two specific point mutations in exons VII and XI respectively, as found in the homologous sequence of the v-abl oncogene. We therefore sought evidence for analogous point mutations in the ABL gene in patients with Ph-negative, BCR-negative CML (n = 25), Ph-negative ALL (n = 18) and in Ph-positive CML in transformation (n = 28). We used restriction fragment length polymorphism and single strand conformational polymorphism techniques to analyse DNA amplified fragments of selected ABL coding regions from leukaemia cells. We identified only normal wild-type DNA sequences. The absence of these transforming point mutations does not exclude the possibility that the ABL gene in such patients could be activated by other means.
Leukemia 1992 Aug
PMID:Specific point mutations that activate v-abl are not found in Philadelphia-negative chronic myeloid leukaemia, Philadelphia-negative acute lymphoblastic leukaemia or blast transformation of chronic myeloid leukaemia. 135 50

Minimal residual disease (MRD) in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1 ALL) who received allogeneic (n = 9) or autologous (n = 6) bone marrow transplantation (BMT) was evaluated by the polymerase chain reaction (PCR) for the bcr-abl transcript. Twelve patients received BMT at the time of hematologic and cytogenetic remission. However, MRD was detected in 8 of 10 patients evaluated. Seven patients, including three who had MRD before BMT, continue to have a disease-free survival 5 to 64 months after BMT. Twenty-one specimens obtained from these patients at various times after BMT did not show MRD. In three patients, MRD detected just before BMT seems to be eradicated by BMT protocol. The other eight patients developed cytogenetic or hematologic relapses 2 to 8 months after BMT. Seven of 14 samples from these patients demonstrated MRD, which preceded clinical relapse by 3 to 9 weeks. Thus, this technique for the detection of MRD appears to be useful for the more precise assessment of various antileukemia therapies and for early detection of leukemia recurrence.
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PMID:Detection of Philadelphia chromosome-positive acute lymphoblastic leukemia by polymerase chain reaction: possible eradication of minimal residual disease by marrow transplantation. 137 20

Expression of the bcr-abl oncogene in multipotent progenitor cells (MPPCs) is implicated as a key event in the development of chronic myelogenous leukemia. Bone marrow enriched for MPPCs was infected with a retrovirus that carried bcr-abl. The mixed-lineage colonies that resulted were responsive to growth factors and could differentiate. These cells later became growth factor-independent but, when injected into severe combined immunodeficient mice, were not leukemogenic. Thus, the presence of bcr-abl alone does not cause growth factor independence, although it initiates a stepwise process. This system may prove useful in the study of other oncogenes that cause leukemia.
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PMID:Initiation of deregulated growth of multipotent progenitor cells by bcr-abl in vitro. 137 94


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