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)

Chronic myeloid leukemia (CML) is defined for many years as BCR-ABL1 positive disease, but older publications refer to a poor prognosis, clinically heterogeneous entity termed 'BCR-ABL1 negative CML' constituting about 5% of CML cases. Apart from very rare CML cases with cytogenetically cryptic, atypical variant BCR-ABL1 fusions that had been inadvertently missed during the diagnostic work up, most of these cases would now be classified as a subtype of myelodysplastic/myeloproliferative neoplasm (MDS/MPN), such as atypical CML (aCML), chronic myelomonocytic leukemia (CMML), or chronic neutrophilic leukemia (CNL). A minority would be classified as systemic mastocytosis with associated hematological neoplasm (SM-AHN), myeloid/lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, FGFR1 or with PCM1-JAK2 (MLN-eo), or chronic eosinophilic leukemia not otherwise specified (CEL-NOS).1.
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PMID:Update on CML-Like Disorders. 3286 48

Expression of the p210 BCR/ABL1 fusion protein has been described in virtually all patients with chronic myelogenous leukemia (CML). Previous studies have identified a guanine nucleotide exchange factor (RhoGEF) domain within BCR that is retained in p210 BCR/ABL1. Missense mutations at residues T654 (T654K) and F547 (F547L) within this domain have been reported in a CML patient in blast crisis (BC). In this study, we have evaluated p210 BCR/ABL1 constructs that contain these substitutions in a murine bone marrow transplantation (BMT) model of CML. The mutants exhibit normal expression and tyrosine kinase activity but altered signaling. When examined in the BMT assay, mice that express the mutants exhibit earlier onset of disease but have significantly extended lifespans relative to mice that express unmodified p210 BCR/ABL1. While mice that express p210 BCR/ABL1 exhibit neutrophilia that progresses to a less differentiated phenotype at death, disease in the mutant mice is characterized by eosinophilia with no maturation arrest. This observation was confirmed in vitro using myeloid cells and was associated with enhanced p53 phosphorylation and G1/S arrest. These results suggest that residues within the RhoGEF domain of p210 BCR/ABL1 can influence disease progression.
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PMID:Examination of clinically-derived p210 BCR/ABL1 RhoGEF mutations in a murine bone marrow transplantation model of CML. 3289 49

Haematological neoplasms are characterised by the presence of recurrent chromosomal abnormalities, making cytogenetics essential for establishing the diagnosis and prognosis. Chromosome banding analysis is mandatory for chronic myeloid leukaemia, neoplasms with eosinophilia, myelodysplastic syndromes and acute leukaemias. In contrast, in other myeloid neoplasms, chronic lymphocytic leukaemia, non-Hodgkin lymphoma and multiple myeloma, the study must be complemented with fluorescence in situ hybridization and/or microarrays, which can overcome some of the shortcomings of banding analysis to identify potential cryptic alterations or reciprocal translocations. In the genomic era, novel technologies such as next generation sequencing are now being used in clinical routine analysis, since they offer the possibility of studying mutations and copy number alterations in a single study at a higher resolution and/or sensitivity. However, they require highly qualified staff and further standardisation, especially regarding data analysis, thereby limiting their current applicability.
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PMID:Cytogenetics in the genomic era. 3303 85


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