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

The molecular hallmark of CML is the BCR-ABL fusion gene, usually with specific breakpoints within ABL intron 1 and BCR introns b2, b3, and e19. The amplification of the BCR-ABL hybrid gene resulting from additional copies of the Ph chromosome has been identified as a mechanism for imatinib (IM) resistance. Cytogenetic clonal evolution correlates with the accelerated phase of leukemia, whereas deletions in the derivative chromosome 9 are associated with a poor prognosis. Relevance in IM therapy is unclear. We report a case of a 39-year-old male with chronic phase CML. Cytogenetic studies showed a complex karyotype with additional copies of the Ph chromosome, sextasomy 8, and ASS gene deletion. An unusual aberrant fusion gene product was derived from the joining of BCR exon 13 (b2) and ABL exon 3 (a3). During IM treatment, the patient was monitored in 3- to 6-month intervals. Major cytogenetic response was achieved after 5 months; complete cytogenetic and molecular remission was reached after 8 months; after 22 months, normal karyotype and absence of the BCR-ABL product continued. Our data seem to confirm the data of others in regards to the b2a3 breakpoint, suggesting a better prognosis, regardless of other unfavorable factors.
 ...
PMID:Complete cytogenetic and molecular response after imatinib treatment for chronic myeloid leukemia in a patient with atypical karyotype and BCR-ABL b2a3 transcript. 1745 51

An increased platelet number in blood depends on a limited spectrum of causes, which aren't always simple to identify. Secondary thrombocytosis is a reactive process in relation with acute or chronic inflammatory diseases, or asplenia. The infrequent inherited thrombocytoses disorders are suspected when similar cases are observed in the same family. However, the most frequent causes of chronic thrombocytosis in adults are the so-called chronic myeloproliferative syndromes (chronic myelocytic leukaemia, polycythemia vera, primary myelofibrosis, essential thrombocytemia), and to a lesser extent, myelodysplastic syndromes. In the course of these disorders, thrombocytosis is often the first recognized abnormality. Chronic myelocytic leukaemia is easily diagnosed owing to the presence of either the Philadelphia chromosome or the BCR-ABL fusion gene product. The next step still relies upon a distinction according to the PVSG or the WHO criteria of Polycythemia Vera (PV) and Idiopathic myelo fibrosis (IMF) to finally confirm genuine Essential Thrombocythemia (ET). The recent description of the V617F mutation of JAK2 in 90% of PV patients, 43 to 67% with IMF and 50% of ET diagnosed according to either the PVSG or the WHO criteria is a definite characteristic of clonality now accessible in haematology practice. However, this mutation is neither specific nor constant in any of the Philadelphia negative myeloproliferative disorders, which outlines the importance of the WHO criteria of megakaryocytic abnormalities on bone marrow biopsy as the hallmark of Ph negative MPDs. The exclusion of PV and of IMF, including pre fibrotic and early fibrotic forms is still required for the diagnosis of "true" ET. Disease stratification and treatment strategy are targeted on the evaluation and prevention of vascular complications. Acute leukaemia or myelodysplasia, and other clonal progressions like myelofibrotic transformation, are infrequent and delayed events. However, according to the present data, the risk of fibrotic progression or of leukaemic transformation is not related to the mutation status of ET patients.
 ...
PMID:[Essential thrombocythemia. Contribution of the V617F JAK2 mutation to the pathophysiology, diagnosis and outcome]. 1807 52

Lineage switch from acute lymphoblastic leukemia (ALL) to acute myeloid leukemia (AML) is very rare. We report a case of a 9 yr-old ALL patient relapsed as acute myelomonocytic leukemia. At the initial diagnosis, the blast cell morphology and immunophenotype were consistent with the diagnosis of typical ALL (L1 subtype according to FAB classification). The BCR-ABL fusion gene was not found by reverse transcription-PCR. Complete remission (CR) was achieved after induction and consolidation chemotherapy (Children's Cancer Study Group 1891 protocol, CCG1891). Nine months, which is a very short time compared with other cases in the literatures, after the diagnosis of ALL, she relapsed with completely different blasts (typical AML, M4 according to FAB classification) in morphology, cytochemistry, and immunophenotyping. The karyotype has changed from 56,XY,+X,+Y,+Y,+4,+8,+10, +14,+17,-20,+21,+21,+21[6]/57,idem,+Y[19] to 46,XY,t(8;16)(p11.2;p13.1)[19]/46,XY[1], showing unrelated chromosomal abnormality to the karyotype at the initial diagnosis. Moreover, both findings were quite specific for each common cell ALL and acute myelomonocytic leukemia. These findings support that this case is completely different leukemic clones occurred at each leukemic expression. The treatment with AML 2000 protocol chemotherapy failed, and he underwent the chemotherapy with the combination of high dose cytarabine and mitoxantrone and has been in CR state for 21 months, until now.
 ...
PMID:A case of lineage switch from acute lymphoblastic leukemia to acute myeloid leukemia. 1809 59

Biphenotypic acute leukemia (BAL) is a subtype of leukemia of ambiguous lineage in the World Health Organization classification system. About one third of the cases have the Philadelphia chromosome, and some cases are associated with other structural abnormalities involving 11q23. BAL is known to have a poor prognosis in both children and adults. According to the previously reported BAL cases with positive BCR-ABL fusion gene, most of the BCR-ABL mRNA transcript type was e1a2. So, we describe here a 30-year-old adult BAL case with the karyotype 46,XY,t(9;22)(q34;q11.2) resulting in a very rare b3a2 type of BCR-ABL mRNA transcript.
 ...
PMID:[Biphenotypic Acute Leukemia with BCR-ABL mRNA Transcript b3a2 Type: A Case Report with Review of the Literature.]. 1815 34

We report a rare case of adult Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) with an e1a3 fusion transcript. A 25-year-old female consulted our hospital for leukocytosis and thrombocytopenia. She was diagnosed with Ph-positive precursor B cell ALL. The patient's BCR-ABL fusion gene showed the e1a3 transcript. She received bone marrow transplantation (BMT) in the first complete remission (CR). However, the disease relapsed 4 months later, and she received a second BMT in the second CR, which caused lethal venoocculusive disease. The duration of the total clinical course was 18 months. We established a new cell line from the patient's leukemic cells at the time of relapse, which is very rare and useful for study as an atypical Ph-positive ALL model. The literature on Ph-positive leukemia lacking ABL exon 2 was also reviewed.
 ...
PMID:A variant transcript, e1a3, of the minor BCR-ABL fusion gene in acute lymphoblastic leukemia: case report and review of the literature. 1825 7

Chronic myelogenous leukemia (CML) is a hematopoietic stem cell malignancy driven by the BCR-ABL fusion tyrosine kinase. The central role played by BCR-ABL1 in the pathogenesis of CML facilitated the development of the tyrosine kinase inhibitor (TKI) imatinib mesylate, the first actual targeted therapy in cancer history. Imatinib competes with ATP at the active site of BCR-ABL1 kinase. Despite outstanding clinical results, imatinib as well as other BCR-ABL1 TKIs have been associated with limited rates of complete molecular response and the development of mutations within the kinase domain of BCR-ABL1 that impairs TKI binding. To override such drawbacks, an array of novel non-ATP-competitive therapies with distinct mechanisms of action is undergoing preclinical, and in some cases, early clinical stages of development. This review focuses on the most promising among such therapeutics.
Leukemia 2008 May
PMID:Experimental non-ATP-competitive therapies for chronic myelogenous leukemia. 1832 96

Chronic myeloid leukemia (CML) is a clonal disorder characterized by proliferation of hematopoietic cells that possess the BCR-ABL fusion gene resulting in the production of a 210 kDa chimeric tyrosine kinase protein. CML, when left untreated, progresses to a blast phase during which the disease turns aggressive and shows poor response to known treatment regimens. We have studied a Siddha herbal agent, Semecarpus anacardium Linn. nut milk extract (SA) for its antileukemic activity and its effect on the changes in energy metabolism in leukemic mice. Leukemia was induced in BALB/c mice by tail vein injection of BCR-ABL(+) 12B1 murine leukemia cell line. This resulted in an aggressive leukemia, similar to CML in blast crisis, myeloid subtype, confirmed by histopathological study and RT-PCR for the p210 mRNA in the peripheral blood, spleen and liver. Leukemia-bearing mice showed a significant increase in lipid peroxides, glycolytic enzymes, a decrease in gluconeogenic enzymes and significant decrease in the activities of TCA cycle and respiratory chain enzymes as compared to control animals. SA treatment was compared with standard drug imatinib mesylate. SA administration to leukemic animals resulted in clearance of the leukemic cells from the bone marrow and internal organs on histopathological examination and this was confirmed by RT-PCR for the p210 mRNA. Treatment with SA significantly reversed the changes seen in the levels of the lipid peroxides, the glycolytic enzymes, the gluconeogenic enzymes and the mitochondrial enzymes. These effects are probably due to the flavonoids, polyphenols and other compounds present in SA which result in total regression of leukemia and correction of the alterations in energy metabolism. Study of animals treated with SA alone did not reveal any adverse effects. On the basis of the observed results, SA can be considered as a readily accessible, promising and novel antileukemic chemotherapeutic agent.
 ...
PMID:Restoration of energy metabolism in leukemic mice treated by a siddha drug--Semecarpus anacardium Linn. nut milk extract. 1835 58

We describe a novel electrochemical branched-DNA (bDNA) assay for polymerase chain reaction (PCR)-free detection and quantification of p185 BCR-ABL leukemia fusion transcripts in the population of messenger ribonucleic acid (mRNA) extracted from cell lines. The bDNA amplifier carrying high loading of alkaline phosphatase (ALP) tracers was used to amplify the target signal. The targets were captured on microplate well surfaces through cooperative sandwich hybridization prior to the labeling of bDNA. The activity of captured ALP was monitored by square-wave voltammetric (SWV) analysis of the electroactive enzymatic product in the presence of 1-naphthyl phosphate. The voltammetric characteristics of substrate and enzymatic product as well as the parameters of SWV analysis were systematically optimized. A detection limit of 1 fM (1 x 10(-19) mol of target transcripts in 100 microL) and a 3-order-wide dynamic range of target concentration were achieved by the electrochemical bDNA assay. Such limit corresponded to approximately 17 fg of the p185 BCR-ABL fusion transcripts. The specificity and sensitivity of assay enabled direct detection of target transcripts in as little as 4.6 ng of mRNA population without PCR amplification. In combination with the use of a well-quantified standard, the electrochemical bDNA assay was capable of direct use for a PCR-free quantitative analysis of target transcripts in mRNA population. A mean transcript copy number of 62,900/ng of mRNA was determined, which was at least 50-fold higher than that of real-time quantitative PCR (qPCR). The finding was consistent with the underestimation of targets by qPCR reported earlier. In addition, the unique design based on bDNA technology increases the assay specificity as only the p185 BCR-ABL fusion transcripts will respond to the detection. The approach thus provides a simple, sensitive, accurate, and quantitative tool alternative to the qPCR for early disease diagnosis.
 ...
PMID:Electrochemical branched-DNA assay for polymerase chain reaction-free detection and quantification of oncogenes in messenger RNA. 1900 91

Chronic myeloid leukemia (CML) is typified by robust marrow and extramedullary myeloid cell production. In the absence of therapy or sometimes despite it, CML has a propensity to progress from a relatively well tolerated chronic phase to an almost uniformly fatal blast crisis phase. The discovery of the Philadelphia chromosome followed by identification of its BCR-ABL fusion gene product and the resultant constitutively active P210 BCR-ABL tyrosine kinase, prompted the unraveling of the molecular pathogenesis of CML. Ground-breaking research demonstrating that BCR-ABL was necessary and sufficient to initiate chronic phase CML provided the rationale for targeted therapy. However, regardless of greatly reduced mortality rates with BCR-ABL targeted therapy, most patients harbor quiescent CML stem cells that may be a reservoir for disease progression to blast crisis. While the hematopoietic stem cell (HSC) origin of CML was first suggested over 30 years ago, only recently have the HSC and progenitor cell-specific effects of the molecular mutations that drive CML been investigated. This has provided the impetus for investigating the genetic and epigenetic events governing HSC and progenitor cell resistance to therapy and their role in disease progression. Accumulating evidence suggests that the acquired BCR-ABL mutation initiates chronic phase CML and results in aberrant stem cell differentiation and survival. This eventually leads to the production of an expanded progenitor population that aberrantly acquires self-renewal capacity resulting in leukemia stem cell (LSC) generation and blast crisis transformation. Therapeutic recalcitrance of blast crisis CML provides the rationale for targeting the molecular pathways that drive aberrant progenitor differentiation, survival and self-renewal earlier in disease before LSC predominate.
 ...
PMID:Chronic myeloid leukemia stem cells. 1907 22

We report a clinical case of chronic myelogenous leukaemia (CML) with regional B-lymphoblastic transformation. Peripheral leukocytosis of 160 x 10(9)/L, splenomegaly and fatigue suggested CML. In peripheral blood and bone marrow smears, white blood cells in all maturation stages and only few blasts were seen and therefore the diagnosis of chronic phase CML was proposed. Cytogenetics performed on peripheral blood cells revealed the characteristic t(9;22)(q34;q11) translocation as solitary abnormality. Analyzing the bone marrow biopsy a focal nodular B-lymphoid blast component was additionally seen. BCR-ABL FISH analysis demonstrated 31% atypical split signals in the B-lymphoid blasts and in the maturing myeloid cells, furthermore, BCR-ABL fusion transcripts were seen in the RT-PCR assay. Imatinib-based therapy led to temporary regression of peripheral leukocytosis. Bone marrow examination 3 weeks after therapy induction demonstrated considerably reduced cellularity and the proportion of B-lymphoid blasts had decreased to 20% of the nuclear cells. BCR-ABL FISH analysis still presented 21% atypical split signals but levels of BCR-ABL transcripts had significantly fallen indicating a rather favourable prognosis. However, 3 months after diagnosis the patient relapsed and developed an immunodeficiency with soor esophagitis and aspergillus pneumonia. A therapy with dasatinib was not successful and the patient died in consequence of immunodeficiency. This report demonstrates the high diagnostic value of bone marrow biopsy in the evaluation of CML. Besides morphology investigation of diverse methods including RT-PCR and FISH performed on diagnostic bone marrow biopsies are obligatory for ideal monitoring of drug response.
 ...
PMID:High diagnostic value of morphologic examination and molecular analysis of bone marrow biopsies in a case of BCR-ABL+ CML with clusters of blasts. 1922 89


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>