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

Activating tyrosine kinase (TK) mutations disrupt cellular proliferation and survival pathways and are increasingly recognized as a fundamental cause of human cancers. Until very recently, the only TK mutations widely observed in myeloid neoplasia were the BCR/ABL1 fusions characteristic of chronic myeloid leukemia and some acute leukemias, and FLT3 activating mutations in a minority of acute myeloid leukemias. Several rare TK mutations are found in various atypical myeloproliferative disorders, but big pieces of the pathobiological puzzle were glaringly missing. In the first half of 2005, one gap was filled in: 7 studies identified the same acquired amino acid substitution (V617F) in the Janus kinase 2 (JAK2) TK in large numbers of patients with diverse clonal myeloid disorders. Most affected patients suffer from the classic BCR/ABL1-negative myeloproliferative disorders (MPD), especially polycythemia vera (74% of n = 506), but a subset of people with essential thrombocythemia (36% of n = 339) or myelofibrosis with myeloid metaplasia (44% of n = 127) bear the identical mutation, as do a few individuals with myelodysplastic syndromes or an atypical myeloid disorder (7% of n = 556). This long-sought common mutation in BCR/ABL1-negative MPD raises many provocative biological and clinical questions, and demands re-evaluation of prevailing diagnostic algorithms for erythrocytosis and thrombocytosis. JAK2 V617F may provide novel molecular targets for drug therapy, and suggests other places to seek cooperating mutations or mutations associated with similar phenotypes. The story of this exciting finding will unfold rapidly in the years ahead, and ongoing developments will be important for all hematologists to understand.
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PMID:JAK2 V617F in myeloid disorders: what do we know now, and where are we headed? 1632 48

FLT3 gene mutations, either internal tandem duplication (ITD) or D835 point mutations, have been studied extensively in acute myeloid leukemia and myelodysplastic syndrome (MDS). Little is known about FLT3 mutations in chronic myeloproliferative diseases (CMPDs) or their relationship with V617F JAK2 mutations. We analyzed bone marrow samples from 142 patients with Philadelphia (Ph) chromosome- CMPD or CMPD/MDS and from 119 patients with Ph+ chronic myeloid leukemia (CML) using a multiplex polymerase chain reaction assay. FLT3 mutations, 11 ITD and 2 D835, were detected in 13 (9.2%) patients with CMPD or CMPD/MDS, 7 in blast phase and 6 in chronic phase. Analyses for JAK2 mutations in 11 of 13 cases were all negative. By contrast, no FLT3 mutations were detected in CML, including 108 chronic and 11 blast phase cases. FLT3 mutations occur in approximately 10% of CMPD and CMPD/MDS but are not observed in JAK2+ CMPD or in CML.
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PMID:Activating FLT3 mutations are detectable in chronic and blast phase of chronic myeloproliferative disorders other than chronic myeloid leukemia. 1693 65

Myeloid malignancies are frequently associated with translocations and mutations of tyrosine kinase genes. Fusion genes involving ABL, ARG, PDGFRs, JAK2, SYK, TRKC, and FGFRs, and gain-of-function mutations of FLT3, KIT and JAK2 have been detected at various rates in myeloproliferative disease and acute myeloid leukemia. Furthermore, abnormal overexpression of tyrosine kinases such as FLT3 has also been reported. These gene products are constitutively activated and potentially transform hematopoietic cells by augmentation of proliferation and enhanced viability. Since the fusion or mutation of tyrosine kinase is a primary and central event in chronic myeloproliferative diseases, targeting the kinase activity has been thought to be an ideal intervention to treat these diseases. The clinical success of imatinib for chronic myeloid leukemia has made this idea a reality, and has accelerated the development of new tyrosine kinase inhibitors (TKIs). Challenging studies with TKIs have also been reported for acute myeloid leukemia. This review will focus on recent trials of TKIs against oncogenic tyrosine kinases (ABL, PDGFRs, FLT3 and KIT) in myeloid malignancies.
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PMID:Developing target therapy against oncogenic tyrosine kinase in myeloid maliganacies. 1707 49

FLT3 is a receptor tyrosine kinase with important roles in hematopoietic stem/progenitor cell survival and proliferation. It is mutated in about 1/3 of acute myeloid leukemia (AML) patients, either by internal tandem duplications (ITD) of the juxtamembrane domain or by point mutations usually involving the kinase domain (KD). Both types of mutation constitutively activate FLT3. Many studies have shown that AML patients with FLT3/ITD mutations have poor cure rates due to relapse. This has led to the development of a number of small molecule tyrosine kinase inhibitors (TKI) with activity against FLT3. Many of these are still in preclinical development, but several have entered clinical phase I and II trials as monotherapy in patients with relapsed AML. Patients with FLT3 mutations in these trials have shown clinical responses, most often a clearing of peripheral blasts, but rarely major reductions of bone marrow blasts. Several studies have shown that FLT3 was successfully inhibited in most patients. However, complete remissions have rarely been achieved in these trials. The difference in responses of chronic myeloid leukemia (CML) patients to BCR-ABL inhibitors compared to FLT3 mutant AML patients to FLT3 inhibitors may be reflective of treating a single gene disease in CML versus multiply altered gene disease in AML. This has led to clinical testing of FLT3 TKI in combination with conventional chemotherapy, with trial designs based on preclinical testing showing synergistic effects between these agents in inducing cytotoxic responses. Several combination trials are ongoing or planned in both relapsed and newly diagnosed FLT3-mutant AML patients.
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PMID:FLT3 mutations: biology and treatment. 1712 58

Human myeloid leukemias provide models of maturation arrest and differentiation therapy of cancer. The genetic lesions of leukemia result in a block of differentiation (maturation arrest) that allows myeloid leukemic cells to continue to proliferate and/or prevents the terminal differentiation and apoptosis seen in normal white blood cells. In chronic myeloid leukemia, the bcr-abl (t9/22) translocation produces a fusion product that is an activated tyrosine kinase resulting in constitutive activation cells at the myelocyte level. This activation may be inhibited by imatinib mesylate (Gleevec, STI-571), which blocks the binding of ATP to the activated tyrosine kinase, prevents phosphorylation, and allows the leukemic cells to differentiate and undergo apoptosis. In acute promyelocytic leukemia, fusion of the retinoic acid receptor-alpha with the gene coding for promyelocytic protein, the PML-RAR alpha (t15:17) translocation, produces a fusion product that blocks the activity of the promyelocytic protein, which is required for formation of the granules of promyelocytes and prevents further differentiation. Retinoic acids bind to the retinoic acid receptor (RAR alpha) component of the fusion product, resulting in degradation of the fusion protein by ubiquitinization. This allows normal PML to participate in granule formation and differentiation of the promyelocytes. In one common type of acute myeloid leukemia, which results in maturation arrest at the myeloid precursor level, there is a mutation of FLT3, a transmembrane tyrosine kinase, which results in constitutive activation of the IL-3 receptor. This may be blocked by agents that inhibit farnesyl transferase. In each of these examples, specific inhibition of the genetically altered activation molecules of the leukemic cells allows the leukemic cells to differentiate and die. Because acute myeloid leukemias usually have mutation of more than one gene, combinations of specific inhibitors that act on the effects of different specific genetic lesions promises to result in more effective and permanent treatment.
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PMID:Leukemia: stem cells, maturation arrest, and differentiation therapy. 1714 56

Protein tyrosine kinases are key participants in signal transduction pathways that regulate cellular growth, activation and differentiation. Aberrant PTK activity resulting from gene mutation (often accompanying chromosome translocation) or overexpression of these enzymes plays an etiologic role in several clonal hematopoietic malignancies. Other than the causative effect of PTK product of the bcr/abl fusion gene on chronic myelogenous leukemia (CML), more evidence suggests that mutated tyrosine kinases are pivotal in the pathogenesis of most of other chronic myeloproliferative disorders, such as chronic myelomonocytic leukemia (CMML) and hypereosinophilic syndrome (HES). And the exciting results in several dependent groups in 2005 showed that a single nucleotide JAK2 somatic mutation (JAK2V617F mutation) was found to be involved in the pathogenesis of polycythemia vera (PV), essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (CIMF). In the leukogenesis of acute myeloid leukemias (AML), the losing of the control of the proliferation of hematopoietic progenitor cells was principally the results of the aberrant PTK activity, such as FLT3 and C-kit overexpression. It works together with the loss of function mutation genes in promoting progenitor cell differentiation to confer AML's phenotypes. These upregulated PTK molecules represent attractive disease-specific targets, to which a new class of therapeutic agents are being developed. This review focuses on abnormal tyrosine kinases that have been involved in the pathogenesis of hematopoietic malignancies.
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PMID:[Abnormal activation of tyrosine kinases and its role in the pathogenesis of hematological malignancies - review]. 1760 88

To study the FLT3 gene expression and its internal tandem duplication in hematologic malignancies and its clinical significance, polymerase chain reaction (PCR) and DNA sequencing were used to detect the FLT3/ITD mutation in blast cells of bone marrow from 86 patients with hematologic malignancies, including 32 cases of acute myeoloid leukemia (AML), 18 cases of acute lymphoblastic leukemia (ALL), 2 cases of acute hybrid leukemia (AHL), 12 cases of myelodysplastic syndromes (MDS), 10 cases of chronic myelogenous leukemia (CML), 3 cases of non-Hodgkin's lymphoma (NHL) and 9 cases of multiple myeloma (MM). The resultes showed that the expression of FLT3/ITD gene could be detected in 5 of 32 (15.6%) AML patients, including 1/7 of M(3), 1/10 of M(4) and 3/10 of M(5). More FLT3 aberrations were found in AML-M(5). No FLT3/ITD was found in 18 cases of ALL, in 2 cases of AHL, in 12 cases of MDS and in 10 cases of CML. No FLT3 was found in 3 cases of NHL and in 9 cases of MM. Sequence analysis in 2 case with abnormal PCR electrophoretic patterns revealed that the ITDs were located within exon 14 from 27 to 63 bp, which was a simple tandem duplication, and did not altered the reading frame. FLT3/ITD was associated with a higher peripheral blood white cell count (p < 0.01), higher percentage of bone marrow blast cells (p < 0.01) and lower complete mission rate. It is concluded that more FLT3/ITD mutation occurs in AML-M(5) patients. Sequence of the mutants is in frame mutation. FLT3/ITD mutation is associated with higher peripheral blood white cell count, higher percentage of bone marrow blast cells and lower complete remission rate, FIT3/IID gene mutation may be used to predict prognosis of patients with AML.
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PMID:[Detection of FLT3 gene mutation in hematologic malignancies and its clinical significance]. 1770 88

Leukemia is thought to arise from malignant stem cells, which have been described for acute and chronic myeloid leukemia (AML and CML) and for acute lymphoblastic leukemia (ALL). Leukemia stem cells (LSCs) are relatively resistant to current chemotherapy and likely contribute to disease relapse and progression. Consequently, the identification of drugs that can efficiently eradicate LSCs is an important priority. In the present study, we investigated the antileukemia activity of the compound TDZD-8. Analysis of primary AML, blast crisis CML (bcCML), ALL, and chronic lymphoblastic leukemia (CLL) specimens showed rapid induction of cell death upon treatment with TDZD-8. In addition, for myeloid leukemias, cytotoxicity was observed for phenotypically primitive cells, in vitro colony-forming progenitors, and LSCs as defined by xenotransplantation assays. In contrast, no significant toxicity was observed for normal hematopoietic stem and progenitor cells. Notably, cell death was frequently evident within 2 hours or less of TDZD-8 exposure. Cellular and molecular studies indicate that the mechanism by which TDZD-8 induces cell death involves rapid loss of membrane integrity, depletion of free thiols, and inhibition of both the PKC and FLT3 signaling pathways. We conclude that TDZD-8 uses a unique and previously unknown mechanism to rapidly target leukemia cells, including malignant stem and progenitor populations.
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PMID:Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione (TDZD-8). 1778 84

Mediators of PI3K/AKT signaling have been implicated in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). Studies have shown that inhibitors of PI3K/AKT signaling, such as wortmannin and LY294002, are able to inhibit CML and AML cell proliferation and synergize with targeted tyrosine kinase inhibitors. We investigated the ability of BAG956, a dual PI3K/PDK-1 inhibitor, to be used in combination with inhibitors of BCR-ABL and mutant FLT3, as well as with the mTOR inhibitor, rapamycin, and the rapamycin derivative, RAD001. BAG956 was shown to block AKT phosphorylation induced by BCR-ABL-, and induce apoptosis of BCR-ABL-expressing cell lines and patient bone marrow cells at concentrations that also inhibit PI3K signaling. Enhancement of the inhibitory effects of the tyrosine kinase inhibitors, imatinib and nilotinib, by BAG956 was demonstrated against BCR-ABL expressing cells both in vitro and in vivo. We have also shown that BAG956 is effective against mutant FLT3-expressing cell lines and AML patient bone marrow cells. Enhancement of the inhibitory effects of the tyrosine kinase inhibitor, PKC412, by BAG956 was demonstrated against mutant FLT3-expressing cells. Finally, BAG956 and rapamycin/RAD001 were shown to combine in a nonantagonistic fashion against BCR-ABL- and mutant FLT3-expressing cells both in vitro and in vivo.
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PMID:Potentiation of antileukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL- and mutant FLT3-expressing cells. 1818 63

Histomorphological evaluation of bone marrow trephines and smears represents the major approach to diagnose the chronic myeloproliferative diseases (CMPD) and the myelodysplastic syndromes (MDS). However, rising insights into molecular pathogenesis of human diseases strengthen the attempt of pathologists to define and to detect underlying defects beyond the microscope. Since discovery of the Philadelphia chromosome in chronic myeloid leukemia as the first specific molecular abnormality ever detected in a human neoplasia the gain of knowledge of molecular pathomechanisms in Philadelphia chromosome negative (Ph-) CMPD was rather sparse. A decisive breakthrough in Ph CMPD was the finding of JAK2 (V617F) derived from a somatic point mutation in the majority of patients with polycythemia vera (P.vera) and half of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). It therefore can not be overestimated that detection of JAK2 (V617F) in a suspective myeloproliferation now enables a clearcut discrimination of a true Ph CMPD from a reactive state, e.g. P.vera from reactive erythrocytosis. Interestingly, a basic principle of molecular defects demonstrable in CMPD and related disorders seems to be the involvement of genes with kinase activities. Some of those genes will be discussed in more detail. In primary MDS, karyotyping via classical cytogenetics is the predominant molecular approach to estimate prognosis, e.g. -Y, del(5q) and del(20q) represent favourable anomalies. Indeed, in 5q- syndromes karyotyping enables definite subtyping and allows clinicians and patients to expect a good prognosis. Until now, dozens of molecular abnormalities such as mutations in AML1, FLT3 and Ras as well as epigenetic alterations of genes have been identified to various degrees in MDS subtypes. Some of them seem to be involved in disease initiation ("master event") and others might indicate disease progression. However, even though useful for further dissection of molecular pathomechanisms the majority of aberrations currently does not serve as potent markers in the daily routine. Nevertheless, in CMPD and MDS the importance of molecular analyses for diagnosis, estimation of prognosis, and disease monitoring will further increase in a foreseeable period of time.
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PMID:[Molecular diagnosis of chronic myeloproliferative diseases and myelodysplastic syndromes]. 1831 8


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