Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.48 (transcriptase)
9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Karyotypic detection of chromosomal 16 abnormalities classically associated with AML M4Eo can be difficult. Characterization of the two genes involved in the inv(16)(p13q22), CBF beta and MYH11, has allowed the detection of fusion transcripts by reverse-transcriptase polymerase chain reaction (RT-PCR). We have analyzed CBF beta-MYH11 fusion transcripts by RT-PCR in myelomonocytic leukemias, with or without eosinophilia, to determine whether their presence correlates with morphology. Fifty-three cases (11 AML M4Eo; 1 AML M4 with atypical abnormal eosinophils (AML M4 "Eo"); 29 AML M4; 8 AML M5; 3 CMML; and 1 AML M2 with eosinophilia) were analyzed. All 11 typical AML M4Eo were CBF beta-MYH11 positive. The single case of AML M4 with distinctive eosinophil abnormalities was negative by karyotype, RT-PCR and fluorescent in situ hybridization (FISH). Three of 29 (10%) AML M4 without abnormal eosinophils were CBF beta-MYH11 positive, 1 of which did not show any apparent chromosome 16 abnormalities by classical metaphase analysis (2 not tested). Both cases tested also showed MYH11 genomic rearrangement. None of the other leukemias were RT-PCR positive. Follow-up of three patient showed residual positivity in apparent complete remission. These data show that CBF beta-MYH11 fusion transcripts occur not only in the vast majority of typical AML M4Eo, but also in approximately 10% of AML M4 without eosinophilic abnormalities, a much higher incidence than the sporadic reports of chromosome 16 abnormalities in AML M4 would suggest. Taken together with the detection of CBF beta-MYH11 transcripts in the absence of apparent chromosome 16 abnormalities by classical banding techniques, these data show that additional screening by either RT-PCR or FISH should be performed in all AML M4, regardless of morphologic features, to allow accurate evaluation of the prognostic importance of this fusion transcript.
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PMID:Detection of the chromosome 16 CBF beta-MYH11 fusion transcript in myelomonocytic leukemias. 785 61

Acute myelomonocytic leukemia with bone marrow eosinophilia (AML-M4Eo in the French-American-British FAB] classification) is frequently associated with pericentric inversion of chromosome 16, inv(16)(p13q22). Recently, the molecular cloning of teh breakpoints has led to the identification of the two fused genes, CBFB on 16q and MYH11 on 16p. We have analyzed 24 patients with AML-M4Eo at diagnosis and 47 patients with AML of other FAB subtypes, by a reverse-transcriptase polymerase chain reaction (RT-PCR) assay for the CBFB/MYH11 fusion mRNAs. Three types of fusion mRNAs were detected in 22 samples of AML-M4Eo (type A, n = 20; type C, n = 1; and type D, n = 1). Among these 22 positive samples, inv(16) was found in the 20 cytogenetically studied cases. No fusion transcript was detected in two patients with AML-M4Eo and in patients with other types of AML. These results confirm that CBFB/MYH11 transcripts (with a predominant type A form) are present in most cases of inv(16) AML. Moreover, detection of the hybrid transcript is closely associated with the finding of abnormal bone marrow (BM) eosinophils in AML-M4Eo as it is not found in other, FAB subtypes of AML, including AML-M4. To assess the presence of type A CBFB/MYH11 fusion transcripts in five AML-M4Eo patients in remission, we designed a sensitive assay combining nested PCR and allele-specific amplification (NPASA). Residual leukemia cells were detected in four patients who were in remission from 4 to 22 months, but not in one patient in long-term remission (5 years). The clinical relevance of persistent CBFB/MYH11 fusion transcripts in remission remains to be established by studying a large prospective series of patients. NPASA provides a useful and sensitive tool for the detection of minimal residual disease in inv(16) AML and, potentially, in other leukemias associated with translocations that result in a predominant fusion transcript.
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PMID:Detection of minimal residual disease in acute myelomonocytic leukemia with abnormal marrow eosinophils by nested polymerase chain reaction with allele specific amplification. 791 48

This report describes a patient presenting with acute myeloid leukaemia (AML-FAB classification M2). Phenotypic markers were positive for cells of the myeloid lineage, but negative for monocyte/macrophage, megakaryocyte, and T-cell lineages. The occasional blast was positive for CALLA. All blasts carried the Philadelphia chromosome (Ph+), with 20% also harbouring a monosomy 7 (a cytogenetic marker for AML). Reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed the presence of two BCR/Abl mRNA transcripts; b2a2, the CML-type and E1a2, the ALL-type. Immunoglobulin (Ig) gene analysis demonstrated the presence of a small population of cells containing rearranged Ig genes. After a short remission, the patient relapsed. At relapse the leukaemia had undergone a major phenotypic switch from AML to ALL, with blasts bearing B-cell markers. Ig gene analysis confirmed a monoclonal population of B-cells. The Ph+ persisted, but the monosomy 7 had disappeared. The same two BCR/Abl mRNA transcripts were found at relapse as at presentation. To our knowledge, this is the first report of an AML simultaneously expressing BCR/Abl transcripts from both the minor and major BCR. The possible mechanisms of this dual expression are discussed.
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PMID:A Ph+ acute myeloid leukaemia expressing both CML-type and ALL-type BCR/ABL mRNA transcripts. 795 Sep 25

Interleukin-11 is a stromal cells derived cytokine which stimulates the proliferation of primitive haemopoietic progenitor cells. For this paper we have studied the constitutive expression of IL-11 mRNA in a panel of wellknown leukaemic cell lines and samples from AML patients at diagnosis. Moreover, the same cellular populations were evaluated for their proliferative response to recombinant-human-(r-hu). IL-11 alone and combined with r-hu-IL-3, granulocyte-macrophage colony stimulating factor (GM-CSF) and stem cell factor (SCF, c-kit ligand). The colony-forming ability of HL60, K562, KG1 cells and eight fresh AML cell populations was assessed by a clonogenic assay in methylcellulose. In eight additional AML cases the number of S-phase leukaemic cells induced by IL-11 was determined by the bromodeoxyuridine (BRDU) incorporation assay after 3d of liquid culture. IL-11, as single cytokine, did not stimulate the colony formation of the three myeloid cell lines under serum-containing and serum-free conditions. In contrast, the proliferation of the leukaemic cells in response to IL-3, GM-CSF and SCF was enhanced by co-incubation with IL-11, and this effect was reversed in blocking experiments by the anti-IL-11 Moab. When tested on primary AML samples, IL-11 alone showed little, if any, proliferative activity. However, it increased the IL-3-dependent blast colony formation in eight out of eight cases and GM-CSF in seven cases. IL-11 also augmented synergistically the number of CFU-L stimulated by SCF in seven cases. A combination of three factors (IL-11, SCF and IL-3) yielded optimal colony formation. The BRDU studies showed the significant increase of AML cells in S-phase when IL-11 was combined with SCF, whereas the two CSF had no activity on their own. Positive interaction was also observed when IL-11 was added to IL-3 supplemented cultures in five out of eight cases tested. Reverse transcriptase-polymerase chain reaction amplification (RT-PCR) demonstrated the constitutive expression of IL-11 mRNA in all the cell lines and 11/12 AML samples studied at diagnosis. These results indicate that IL-11 is expressed in leukaemic myeloid cells and that their proliferation is regulated by the cytokine which acts as a synergistic factor.
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PMID:Interleukin-11 (IL-11) acts as a synergistic factor for the proliferation of human myeloid leukaemic cells. 854 68

Pericentric inversion of chromosome 16 [inv(16)(p13q22)] is seen in patients with acute myelomonocytic leukemia with bone marrow eosinophilia. This inversion juxtaposes the MYH11 gene on p13 and the CBFB gene on q22, resulting in the formation of a chimeric mRNA transcript. We describe a patient with acute myelogenous leukemia (M1), with del(16)(q22), who expressed the chimeric transcript. Reverse transcriptase polymerase chain reaction and the sequencing of its product showed fusion of 5'CBFB at position 495 to 3'MYH11 at position 1201. To our knowledge, this is the first report of an AML (M1) case with del(16) and CBFB/MYH11 rearrangement.
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PMID:CBFB/MYH11 fusion transcripts in a case of acute myelogenous leukemia (M1) with partial deletion of the long arm of chromosome 16. 873 92

Receptor tyrosine kinases (RTK) play an important role in the signal transduction of normal and malignant cells. There are different families of RTKs which are mainly characterized by differences in the ligang-binding extracellular domains. Axl (or UFO/Ark) is the first member of a new class of RTK with two fibronectin type III domains and two immunoglobulin-like domains present at the extracellular domain. The axl-gene has been isolated by means of gene transfection studies using DNA of patients with chronic myelogeneous leukemia. For a previous and the present study, we used a sensitive reverse-transcriptase polymerase chain reaction assay to detect axl's mRNA in cells from normal and malignant hematopoietic tissue. Axl's mRNA expression was mainly detected in myelo-monocytic cells, whereas much weaker transcription was seen in lymphatic cells and in lymphatic leukemias. In normal bone marrow, axl was heavily transcribed in marrow stromal cells. Further, we analysed Axl protein expression using monoclonal antibody M50 in peripheral stem cell harvests; in most harvests, no co-expression of CD34 and Axl was detected. However, in one patient with AML in complete remission, Axl was co-expressed on 80% of the CD34-positive population. These data show that axl is preferentially expressed in monocytes and stromal cells. Furthermore, a fraction of CD34-positive progenitor cells may express Axl. The exact mechanism for transformation of myeloid progenitor cells through Axl, however, remains to be determined.
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PMID:Recent progress on the role of Axl, a receptor tyrosine kinase, in malignant transformation of myeloid leukemias. 913 Jun 17

The two matrix metalloproteinases (MMPs) Mr 72,000 type IV collagenase (MMP-2, gelatinase A) and Mr 92,000 type IV collagenase (MMP-9, gelatinase B) play key roles in tissue remodeling and tumor invasion by digestion of extracellular matrix barriers. We have investigated the production of these two enzymes as well as the membrane-type MMP (MT1-MMP) and the tissue inhibitors of metalloproteinases (TIMPs) TIMP-1 and TIMP-2 in the bone marrow mononuclear cells (BM-MNCs) of patients with acute myeloid leukemia (AML; n = 24), chronic myeloid leukemia (CML; n = 17), myelodysplastic syndromes (MDS; n = 8), and healthy donors (n = 5). Zymographic analysis of BM-MNC-conditioned medium showed that a Mr 92,000 gelatinolytic activity, identified as MMP-9 by Western blotting, was constitutively released from cells of all patients and healthy individuals examined in this study. In contrast, MMP-2 secretion was found to be absent in all samples from healthy donors but present in 8 of 11 (73%) of the samples from patients with primary AML, 7 of 8 (88%) with secondary AML, and only 1 of 5 (20%) cases with AML in remission, indicating MMP-2 to be produced by the leukemic blasts. MMP-2 release was not detected in CML cell-conditioned medium with the exception of two cases, both patients either being in or preceding blast crisis. In MDS, MMP-2 was found in three of eight (38%) of the patients, two of them undergoing progression of disease within 12 months. Quantitative Northern blot analysis in freshly isolated BM-MNCs showed a relatively low constitutive expression of TIMP-1 in all samples, whereas MMP-9 gene transcription was higher in healthy donors and CML samples, than in AML and MDS. Reverse transcriptase-PCR analysis revealed the presence of TIMP-2 mRNA in the majority of MMP-2-releasing BM-MNCs. MT1-MMP expression was present in most samples of patients with MDS or AML but absent in those with secondary AML and CML. Thus, we have shown that BM-MNCs continuously produce MMP-9 and TIMP-1 and demonstrated that leukemic blast cells additionally secrete MMP-2 representing a potential marker for dissemination in myeloproliferative malignancies.
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PMID:Matrix metalloproteinase production by bone marrow mononuclear cells from normal individuals and patients with acute and chronic myeloid leukemia or myelodysplastic syndromes. 1035 46

Somatostatin, a neuropeptide with multiple activities, exerts its function via G-coupled membrane receptors. Five somatostatin receptor subtypes, sst1-5, have been identified. We have recently established that somatostatin acts as a chemoattractant on normal hematopoietic progenitor cells. Here, we studied the expression of somatostatin receptors (sst) on leukemic cells from 16 AML patients. Using fluorescent somatostatin (Fluo-SS) in flow cytometry, we found that sst are expressed in variable amounts on primary AML cells. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis and immunochemistry revealed that only sst subtype 2 is expressed by AML cells. Using a two-chamber in vitro migration assay, we show that AML cells migrated towards a gradient of octreotide, a stable synthetic analogue of somatostatin. The degree of migration correlated with the cell surface density of sst2 as measured by Fluo-SS binding. These findings indicate that somatostatin influences trafficking of AML cells, which may have implications for the distribution of AML cells in the body and for clinical applications of somatostatin and analogues thereof in the context of AML.
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PMID:Somatostatin induces migration of acute myeloid leukemia cells via activation of somatostatin receptor subtype 2. 1136 65

The patient was a 62-year-old man. His hematological data in April 2000 had shown no abnormalities, but he was referred to our hospital because of a fever and leukocytosis in June 2000. The peripheral blood showed 29.8 x 10(9)/L white blood cells, with 68.0% blasts. A bone marrow aspirate showed hypercellularity with a proliferation of large leukemic blasts. The leukemic cells were positive for CD13 (91%), CD33 (54.8%), CD34 (94.5%), and HLA-DR (97.9%). Some leukemic cells (15.6%) also expressed CD14. Cytogenetic analysis revealed 92,XXYY,t(9;22)(q34;q11)x2 in all 20 metaphase cells. Reverse transcriptase polymerase chain reaction analysis detected the minor BCR/ABL messenger RNA (mRNA) but failed to detect the major BCR/ABL mRNA. The patient achieved complete remission after induction chemotherapy, with no evidence of Philadelphia chromosome (Ph) or minor BCR/ABL mRNA. Ph-positive acute myeloid leukemia (Ph-AML) has rarely been reported. Herein, we report a case of Ph-AML with tetraploidy and review the previously reported Ph-AML cases.
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PMID:Philadelphia chromosome-positive acute myeloid leukemia with tetraploidy. 1184 93

The t(10;11)(p12-14;q14-21) is a non-random translocation that results in the fusion of CALM gene on chromosome 11 with AF10 gene on chromosome 10. This translocation is observed in acute myeloid leukemia, acute lymphoblastic leukemia, and lymphoblastic lymphoma. Here we report a patient with t(10;11) who was diagnosed with AML-M4. Reverse transcriptase-polymerase chain reaction (RT-PCR) assay revealed one type of CALM/AF10 and three types of AF10/CALM fusion transcripts. Sequencing analysis for these RT-PCR products determined the breakpoint in CALM at nucleotide (nt) 1926-1927 and in AF10 at nt 423-424. The latter breakpoint was the same as that identified in three monocytic cell lines carrying t(10;11). After achieving complete remission, the patient developed mediastinal emphysema during the course of consolidation therapy, possibly due to the necrosis of his mediastinal mass. Monocytic leukemias with CALM/AF10 fusion are frequently associated with mediastinal invasion. We need to pay special attention to such a complication, even if the chest X-ray is normal at presentation.
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PMID:Monocytic leukemia with CALM/AF10 rearrangement showing mediastinal emphysema. 1255 19


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