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

A clinicopathological follow-up study was performed on 17 patients with chronic myeloid leukaemia (CML) and 23 cases with so-called primary (idiopathic) osteo-/myelofibrosis (OMF) concentrating on a comparison between clinical data and multiple sequential biopsies of the bone marrow. Histological classification of bone marrow lesions was done according to the subtypes proposed by Georgii et al. At clinical diagnosis initial trephine biopsies in CML showed in only 6/17 cases a pronounced granulocytic proliferation or CGL. In 9/23 patients with OMF a so-called hyperplastic or early hypercellular stage was encountered with a mixed megakaryocytic-granulocytic pattern without or with minimal reticulin fibres (CMGM/EMS). The histopathology of this early stage OMF as well as the later evolving advanced fibrosclerotic lesions (AMS/OMS) were by morphological aspects alone not distinguishable from cases with CML showing prominent fibrosclerotic alterations. At presentation 5/17 patients with CML displayed already some degree of reticulin fibre formation (EMS). Following serial trephine biopsies in CML with an increased megakaryocyte proliferation (CMGM), a remarkable tendency for myelofibrosis was present. The dynamics of this fibrosclerotic transformation seem to be variable in CML and OMF likewise. However, they are related to abnormal megakaryopoiesis as well as to duration respectively progress of disease, paralleled by corresponding haematological parameters. This longitudinal case control study emphasizes that histopathology of the bone marrow taken at clinical diagnosis may reflect different stages of chronic myeloproliferative diseases and therefore should be always accompanied by relevant clinical and cytogenetic findings to enable a correct diagnosis.
 ...
PMID:Follow-up studies with sequential bone marrow biopsies in chronic myeloid leukaemia and so-called primary (idiopathic) osteo-myelofibrosis. Evolution of histopathological lesions and clinical course in 40 patients. 318 44

The 8p11 myeloproliferative syndrome (EMS) is associated with three translocations, t(8;13)(p11;q12), t(8;9)(p11;q33), and t(6;8)(q27;p11), that fuse unrelated genes (ZNF198, CEP110, and FOP, respectively) to the entire tyrosine kinase domain of FGFR1. In all cases thus far examined (n = 10), the t(8;13) results in an identical mRNA fusion between ZNF198 exon 17 and FGFR1 exon 9. To determine if consistent fusions are also seen in the variant translocations, we performed RT-PCR on four cases and sequenced the products. For two patients with a t(8;9), we found that CEP110 exon 15 was fused to FGFR1 exon 9. For two patients with a t(6;8), we found that FOP exon 5 (n = 1) or exon 7 (n = 1) was fused to FGFR1 exon 9. To determine if FGFR1 might be involved in other myeloid disorders with translocations of 8p, we developed a two-color FISH assay using two differentially labeled PAC clones that flank FGFR1. Disruption of this gene was indicated in a patient with a t(8;17)(p11;q25) and Ph-negative chronic myeloid leukemia in association with systemic malignant mast cell disease, a patient with acute myeloid leukemia with a t(8;11)(p11;p15), and two cases with T-cell lymphoma, myeloproliferative disorder, and marrow eosinophilia with a t(8;12)(p11;q15) and ins(12;8)(p11;p11p21), respectively. For the patient with the t(8;11), the chromosome 11 breakpoint was determined to be in the vicinity of NUP98. We conclude that 1) all mRNA fusions in EMS result in splicing to FGFR1 exon 9 but breakpoints in FOP are variable, 2) two-color FISH can identify patients with EMS, and 3) the t(8;17)(p11;q25), t(8;11)(p11;p15), t(8;12)(p11;q15), and ins(12;8)(p11;p11p21) are novel karyotypic changes that most likely involve FGFR1.
 ...
PMID:Identification of four new translocations involving FGFR1 in myeloid disorders. 1155 Feb 83

The 8p11 myeloproliferative syndrome (EMS) is an aggressive hematological malignancy caused by the fusion of diverse partner genes to fibroblast growth factor receptor 1 (FGFR1). The partner proteins promote dimerization and ligand-independent activation of FGFR1-encoded tyrosine kinase, deregulating hemopoiesis in a manner analogous to BCR-ABL in chronic myeloid leukemia. Here, we describe the identification of a new FGFR1 fusion gene in a patient who presented with T-cell lymphoblastic lymphoma in conjunction with an acquired ins(12;8)(p11;p11p22). Initial FISH analysis and Southern blotting confirmed that FGFR1 was disrupted. Using 5'-RACE PCR, we identified part of a novel gene, FGFR1OP2, at chromosome band 12p11 that was fused to exon 9 of FGFR1.FGFR1OP2 is predicted to be translated into an evolutionarily conserved protein containing coiled-coil domains but no other recognizable motifs. The presence of the chimeric gene was confirmed by RT-PCR, genomic DNA PCR, and FISH. These data further support the central role of deregulated FGFR1 in the pathogenesis of EMS.
 ...
PMID:Identification of a novel gene, FGFR1OP2, fused to FGFR1 in 8p11 myeloproliferative syndrome. 1503 73

8p11 myeloproliferative syndrome (EMS) is a hematopoietic stem cell disorder characterized by myeloid hyperplasia and non-Hodgkin's lymphoma with chromosomal translocations fusing several genes, most commonly ZNF198, to fibroblast growth factor receptor-1 (FGFR1). However, patients with BCR-FGFR1 fusion present with typical chronic myeloid leukemia (CML). We demonstrate that ZNF198-FGFR1 induces EMS-like disease in mice, with myeloproliferation and T lymphoma arising from common multipotential progenitors. Mutation of FGFR1 Tyr766 attenuates both myeloid and lymphoid diseases, identifying phospholipase C-gamma1 as a downstream effector. Bcr-FGFR1 binds Grb2 via Bcr Tyr177 and induces CML-like leukemia in mice, whereas Bcr-FGFR1/Y177F lacks Grb2 binding and causes EMS-like disease. These results implicate different signaling pathways originating from both kinase and fusion partner in the pathogenesis of CML and EMS.
 ...
PMID:Distinct stem cell myeloproliferative/T lymphoma syndromes induced by ZNF198-FGFR1 and BCR-FGFR1 fusion genes from 8p11 translocations. 1505 Sep 20

Busulfan (1,4-butanediol dimethanesulfonate) has been used widely for the treatment of patients with chronic myelogenous leukemia. Busulfan is bifunctional and thus may effectively induce DNA damage, which may play an important role in the cytotoxicity. In this study, we compared the cytotoxicity of bifunctional busulfan with that of monofunctional ethyl methanesulfonate (EMS) in human promyelocytic leukemia HL-60 cells. Busulfan showed a significant inhibitory effect on cell growth, whereas the cells grew in the presence of EMS. To clarify the mechanism of cytotoxicity of busulfan, we investigated DNA damage induced by busulfan using 32P-5'-end-labeled DNA fragments obtained from the human p16 tumor suppressor gene. Busulfan induced DNA damage dose-dependently, whereas EMS caused little DNA damage. DNA-sequencing experiments using piperidine and 3-methyladenine DNA glycosylase indicated that busulfan caused double-base lesions mainly at 5'-GA-3' and, to a lesser extent, at 5'-GG-3' sequences. Time of flight mass spectrometry confirmed that busulfan forms an intrastrand cross-link at the 5'-GA-3' sequence, in addition to mono-alkylation. The mechanism and the role of cross-linking at the 5'-GA-3' sequence are discussed in relation to the cytotoxicity induced by busulfan.
 ...
PMID:DNA intrastrand cross-link at the 5'-GA-3' sequence formed by busulfan and its role in the cytotoxic effect. 1513 75

The 8p11 myeloproliferative syndrome (EMS), a rare myeloproliferative disease, generally progresses rapidly and is characterized by chromosomal translocations of the fibroblast growth factor receptor 1 (FGFR1) gene. The FGFR1 gene is located at chromosome 8p11 and may fuse with distinct partner genes. The breakpoint cluster region gene located at chromosome 22 is one of these partner genes. The patients' clinical phenotype is primarily dependant on the partner gene that translocates with FGFR1. Of all the available examinations, determination of the chromosome karyotype is most essential for the diagnosis of EMS. In addition, regarding treatment, allogeneic hematopoietic stem cell transplantation is currently the optimal method. The present study presented a case of 8p11 myeloproliferative syndrome with t(8;22)(p11;q11). This represents a total of 8 and 11 chromosomal translocations, which form a BCR/FGFR1 fusion gene in the patient to produce the abnormal karyotype: 46,XY,t(8;22)(p11;q11). The difference between the current case and other EMS incidences is that the patient progressed slowly and the clinical manifestation was similar to chronic myeloid leukemia (CML).
 ...
PMID:8p11 Myeloproliferative syndrome with t(8;22)(p11;q11): A case report. 3011 93