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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies frequently characterized by a mutation in JAK2 (JAK2V617F). Peripheral blood (PB) CD34(+) cells from patients with polycythemia vera (PV) and primary myelofibrosis (PMF) generated in vitro significantly fewer mast cells (MCs) than normal PB CD34(+) cells. The numbers of MC progenitors assayed from MPN CD34(+) cells were, however, similar to that assayed from normal CD34(+) cells. A higher percentage of the cultured MPN MCs expressed FcvarepsilonRIalpha, CD63 and CD69 than normal MCs, suggesting that cultured MPN MCs are associated with an increased state of MC activation. Further analysis showed that a higher proportion of cultured PV and PMF MCs underwent apoptosis in vitro. By using JAK2V617F, MplW515L and chromosomal abnormalities as clonality markers, we showed that the malignant process involved MPN MCs. JAK2V617F-positive MC colonies were assayable from the PB CD34(+) cells of each of the 17 JAK2V617F positive MPN patients studied. Furthermore, erlotinib, a JAK2 inhibitor, was able to inhibit JAK2V617F-positive PV MC progenitor cells, indicating that malignant MC progenitor cells are a potential cellular target for such JAK2 inhibitor-directed therapy.
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PMID:Involvement of mast cells by the malignant process in patients with Philadelphia chromosome negative myeloproliferative neoplasms. 1938 66

Chronic myelogenous leukemia (CML) is a hematological malignancy that begins as indolent chronic phase (CP) but inevitably progresses to fatal blast crisis (BC). p210BCR/ABL, a chimeric protein with enhanced kinase activity, initiates CML CP, and additional genetic alterations account for progression to BC, but the precise mechanisms underlying disease evolution are not fully understood. In the present study, we investigated the possible contribution of dysfunction of Bcl11b, a zinc-finger protein required for thymocyte differentiation, and of H2AX, a histone protein involved in DNA repair, to the transition from CML CP to BC. For this purpose, we crossed CML CP-exhibiting p210BCR/ABL transgenic (BA(tg/-)) mice with Bcl11b heterozygous (Bcl11b(+/-)) mice and H2AX heterozygous (H2AX(+/-)) mice. Interestingly, p210BCR/ABL transgenic, Bcl11b heterozygous (BA(tg/-)Bcl11b(+/-)) mice and p210BCR/ABL transgenic, H2AX heterozygous (BA(tg/-)H2AX(+/-)) mice frequently developed CML BC with T-cell phenotype and died in a short period. In addition, whereas p210BCR/ABL was expressed in all of the leukemic tissues, the expression of Bcl11b and H2AX was undetectable in several tumors, which was attributed to the loss of the residual normal allele or the lack of mRNA expression. These results indicate that Bcl11b and H2AX function as tumor suppressor and that haploinsufficiency and acquired loss of these gene products cooperate with p210BCR/ABL to develop CML BC.
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PMID:Haploinsufficiency and acquired loss of Bcl11b and H2AX induces blast crisis of chronic myelogenous leukemia in a transgenic mouse model. 1943 95

The discovery of the Janus kinase (JAK)2 V617F mutation in patients with myeloproliferative neoplasms was a major milestone in understanding the biology of those disorders. Several groups simultaneously reported on the high incidence of this mutation in patients with myeloproliferative neoplasms: almost all patients with polycythemia vera harbor the mutation and about 50% of patients with essential thrombocythemia and primary myelofibrosis have the mutation, making the development of JAK2 tyrosine kinase inhibitors an attractive therapeutic goal. In addition, inhibition of JAK2 kinase may have a therapeutic role in other hematologic malignancies, such as chronic myeloid leukemia or lymphoma. A number of molecules that inhibit JAK2 kinase have been described in the literature, and several are being evaluated in a clinical setting. Here, we summarize current clinical experience with JAK2 inhibitors.
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PMID:Prospect of JAK2 inhibitor therapy in myeloproliferative neoplasms. 1944 82

Janus kinase 2 (JAK2) plays a crucial role in the pathomechanism of myeloproliferative disorders and hematologic malignancies. A somatic mutation of JAK2 (Val617Phe) was previously shown to occur in 98% of patients with polycythemia vera and 50% of patients with essential thrombocythemia and primary myelofibrosis. Thus, effective JAK2 kinase inhibitors may be of significant therapeutic importance. Here, we applied a structure-based virtual screen to identify novel JAK2 inhibitors. One JAK2 inhibitor in particular, G6, demonstrated remarkable potency as well as specificity, which makes it as a potential lead candidate against diseases related to elevated JAK2 tyrosine kinase activity.
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PMID:Identification of a novel inhibitor of JAK2 tyrosine kinase by structure-based virtual screening. 1944 17

The preferentially expressed antigen in melanoma (PRAME) is expressed in several hematologic malignancies, but either is not expressed or is expressed at only low levels in normal hematopoietic cells, making it a target for cancer therapy. PRAME is a tumor-associated antigen and has been described as a corepressor of retinoic acid signaling in solid tumor cells, but its function in hematopoietic cells is unknown. PRAME mRNA expression increased with chronic myeloid leukemia (CML) disease progression and its detection in late chronic-phase CML patients before tyrosine kinase inhibitor therapy was associated with poorer therapeutic responses and ABL tyrosine kinase domain point mutations. In leukemia cell lines, PRAME protein expression inhibited granulocytic differentiation only in cell lines that differentiate along this lineage after all-trans retinoic acid (ATRA) exposure. Forced PRAME expression in normal hematopoietic progenitors, however, inhibited myeloid differentiation both in the presence and absence of ATRA, and this phenotype was reversed when PRAME was silenced in primary CML progenitors. These observations suggest that PRAME inhibits myeloid differentiation in certain myeloid leukemias, and that its function in these cells is lineage and phenotype dependent. Lastly, these observations suggest that PRAME is a target for both prognostic and therapeutic applications.
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PMID:The preferentially expressed antigen in melanoma (PRAME) inhibits myeloid differentiation in normal hematopoietic and leukemic progenitor cells. 1962 8

Ph-positive chronic myeloid leukemia (CML) and Ph-negative chronic myeloproliferative diseases (MPDs), characterized in many cases by the presence of the JAK2(V617F) mutation, have many features in common and yet also show fundamental differences. In this review, we pose five discrete and related questions relevant to both categories of hematological malignancy, namely: What are the mechanisms that underlie disease progression from a relatively benign or chronic phase? By what therapeutic methods might one target residual leukemia stem cells in CML? Is JAK2(V617F) the original molecular event in MPD? What epigenetic events must have a role in dictating disease phenotype in MPDs? And finally, Will the benefits conferred by current or future JAK2(V617F) inhibitors equal or even surpass the clinical success that has resulted from the use of tyrosine kinase inhibitors in CML? These and others questions must be addressed and in some cases should be answered in the foreseeable future.
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PMID:Chronic myeloproliferative diseases with and without the Ph chromosome: some unresolved issues. 1964 23

The chromosomal abnormality der(9)t(1;9)(q11;q34) is a rare occurrence in patients with hematologic malignancies. As far as we know, only 3 cases of acute myeloid leukemia, 1 case of polycythemia vera, and 1 case of multiple myeloma with this derivative chromosome have been reported in the literature. Here we report the first case of der(9)t(1;9)(q11;q34) in a patient with chronic myelomonocytic leukemia (CMML). A 45-yr-old man was brought to our hospital for evaluation of pancytopenia and monocytosis. The patient's persistent monocytosis in peripheral blood and his bone marrow findings were consistent with the diagnosis of CMML. Chromosome study results repeatedly showed 46,XY,der(9)t(1;9)(q11;q34). In addition, the BCR/ABL fluorescent in situ hybridization (FISH) pattern of the interphase cells was interpreted as: "nuc ish(ABL, BCR) x 2[292/300]," consistent with the normal signal patterns found in 97% of the nuclei examined. For further evaluation, multi-color FISH (mFISH) analysis was performed and it showed the distinct unbalanced derivative chromosome der(9)t(1;9)(q11;q34) in 5 metaphase cells analyzed. Not only does this show an extraordinary type of trisomy 1q, but it reveals a rare recurrent case of der(9)t(1;9)(q11;q34) in patients with monocytic-lineage leukemia. Further studies are needed to evaluate the prognosis, survival, and treatment response of such patients with der(9)t(1;9)(q11;q34).
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PMID:Chronic myelomonocytic leukemia with der(9)t(1;9)(q11;q34) as a sole abnormality. 1966 17

The recent and rapid development of molecularly targeted therapy is best illustrated by advances in the management of haematological malignancy. In myeloid diseases we have seen dramatic improvements in the overall survival and quality of life for patients with chronic myeloid leukaemia treated with ABL and Src/ABL kinase inhibitors and we are poised to discover whether JAK2 inhibitors may offer similar benefit in myeloproliferative diseases. For acute myeloid leukaemia, the introduction of ATRA and myelotarg have had major impacts on the design of therapy regimens and many novel targeted agents, including farnesyl transferase, FLT3 and histone deacetylase inhibitors, are now in clinical trial. In lymphoid malignancies the highlight has been the introduction of rituximab, with significant improvements in the management of non-Hodgkin lymphoma and chronic lymphocytic leukaemia. The last 10 years has experienced a rapidly expanding interest and acceptance that leukaemic stem cells, including an improved ability to target them, may hold the key to improved response and reduced relapse rates across both myeloid and lymphoid disease. We now eagerly anticipate an era in which a wealth of preclinical discoveries are progressed to the clinic.
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PMID:Targeted therapy in haematological malignancies. 2004 51

Somatic mutations in TET2 occur in patients with myeloproliferative neoplasms and other hematologic malignancies. It has been suggested that TET2 is a tumor suppressor gene and mutations in TET2 precede the acquisition of JAK2-V617F. To examine the order of events, we performed colony assays and genotyped TET2 and JAK2 in individual colonies. In 4 of 8 myeloproliferative neoplasm patients, we found that some colonies with mutated TET2 carried wild-type JAK2, whereas others were JAK2-V617F positive, indicating that TET2 occurred before JAK2-V617F. One of these patients carried a germline TET2 mutation. However, in 2 other patients, we obtained data compatible with the opposite order of events, with JAK2 exon 12 mutation preceding TET2 mutation in one case. Finally, in 2 of 8 patients, the TET2 and JAK2-V617F mutations defined 2 separate clones. The lack of a strict temporal order of occurrence makes it unlikely that mutations in TET2 represent a predisposing event for acquiring mutations in JAK2.
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PMID:Clonal analysis of TET2 and JAK2 mutations suggests that TET2 can be a late event in the progression of myeloproliferative neoplasms. 2131 Sep 37

Single nucleotide polymorphism arrays (SNP-A) have recently been widely applied as a powerful karyotyping tool in numerous translational cancer studies. SNP-A complements traditional metaphase cytogenetics with the unique ability to delineate a previously hidden chromosomal defect, copy neutral loss of heterozygosity (CN-LOH). Emerging data demonstrate that selected hematologic malignancies exhibit abundant CN-LOH, often in the setting of a normal metaphase karyotype and no previously identified clonal marker. In this review, we explore emerging biologic and clinical features of CN-LOH relevant to hematologic malignancies. In myeloid malignancies, CN-LOH has been associated with the duplication of oncogenic mutations with concomitant loss of the normal allele. Examples include JAK2, MPL, c-KIT, and FLT3. More recent investigations have focused on evaluation of candidate genes contained in common CN-LOH and deletion regions and have led to the discovery of tumor suppressor genes, including c-CBL and family members, as well as TET2. Investigations into the underlying mechanisms generating CN-LOH have great promise for elucidating general cancer mechanisms. We anticipate that further detailed characterization of CN-LOH lesions will probably facilitate our discovery of a more complete set of pathogenic molecular lesions, disease and prognosis markers, and better understanding of the initiation and progression of hematologic malignancies.
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PMID:Copy neutral loss of heterozygosity: a novel chromosomal lesion in myeloid malignancies. 2010 30


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