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

Recently we described the establishment in culture and the immunophenotypic and functional characteristics of a human T-leukemia line TALL-103/2 derived from the T-cell receptor (TCR)-gamma/delta subset of T-lymphocytes. TALL-103/2 cells are absolutely dependent on interleukin 2 (IL-2) for their growth and survival in culture and thus provide a model cell line for studies of IL-2 signal transduction in a TCR-gamma/delta T-cell. In this report, we focus on the regulation of SRC-family protein tyrosine kinases (PTKs) by IL-2. TALL-103/2 cells were found to contain p56-LCK, p59-FYN, p62-YES and p53/56-LYN. Stimulation of growth factor-deprived TALL-103/2 cells with IL-2, however, induced increases in the relative activity only of the p56-LCK kinase. This IL-2-mediated increase in LCK kinase activity was manifested both by increased kinase autophosphorylation and by increased phosphorylation of the exogenous substrate enolase during in vitro kinase assays. Furthermore, immunoblot assays determined that the levels of p56-LCK protein were unaltered by IL-2-treatment, indicating that the measured elevations in LCK kinase activity reflected an increase in the specific activity of this PTK. In TALL-103/2 cells, IL-2 stimulated concentration-dependent increases in p56-LCK activity that displayed rapid and transient kinetics: detectable increases occurred within 1 minute after IL-2 stimulation, peaked at 10 minutes, and declined to baseline levels by 30 minutes. Treatment of TALL-103/2 cells with IL-4 abrogated IL-2-initiated proliferation, but did not inhibit IL-2-mediated activation of p56-LCK.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin 4 inhibits IL-2-induced proliferation of a human T-leukemia cell line without interfering with p56-LCK kinase activation. 142 Sep 98

Unlike many other growth factor receptors, the known subunits of the receptors for the Interleukins IL-2 and IL-3 lack intrinsic tyrosine kinase activity, and yet increases in the phosphorylation of proteins on tyrosines is a rapid event in hematolymphoid cells following stimulation with these lymphokines. Here we show that IL-2 and IL-3 regulate the activity of specific members of the SRC-family of non-receptor protein tyrosine kinases (PTKs). In IL-2-dependent T-cell lines, IL-2 induced rapid and transient increases in the activity of the p56-LCK kinase without influencing the activities of other SRC-like PTKs (p59-FYN, p62-YES) in these T-lymphocytes. In contrast to IL-2's effects on p56-LCK in T-cells, studies of an IL-2-responsive cell line of the B-cell lineage that lacks p56-LCK revealed that IL-2 specifically regulates the activity of the p53/56-LYN kinase. Thus, some flexibility exists in the ability of various SRC-like PTKs to functionally couple to IL-2 signalling pathways. In several IL-3-dependent myeloid-committed leukemic cell lines, IL-3 was found to specifically regulate the activity of the p53/56-LYN kinase without affecting the activities of other SRC-like PTKs (p59/64-HCK, p59-FYN, p62-YES) in these hematopoietic cells. This finding that p53/56-LYN can be regulated by both IL-2 in B-lineage cells and IL-3 in myeloid-committed cells demonstrates that the same SRC-family PTK can participate in signal transduction events mediated via two independent receptor systems. Taken together, our findings imply that the specific combinations of lymphokine receptors and SRC-like PTKs available for coupling with those receptors are coordinately controlled during the differentiation of hematopoietic cells.
Leukemia 1992
PMID:Regulation of SRC-family protein tyrosine kinases by interleukins, IL-2, and IL-3. 160 36

A member of the Src family of protein tyrosine kinases, Lyn is involved in the signaling pathways for cytokine or immunoglobulin-stimulated blood cells. Lyn is especially prominent in B-cell function. We have fine mapped LYN to chromosome 8q11-12 by fluorescence in situ hybridization. Of note, the gene for the pre-B cell growth factor, interleukin 7 (IL-7), has been mapped to 8q12-13. We show that IL-7 increases the protein tyrosine kinase activity of Lyn in the Daudi B-cell line. A third gene, HYRC, whose product may be involved in immunoglobulin rearrangement, has recently been localized to 8q11. We postulate that a lymphoid signaling region exists at 8q11-13.
Leukemia 1994 Nov
PMID:Localization of the human gene for Src-related protein tyrosine kinase LYN to chromosome 8q11-12: a lymphoid signaling cluster? 796 36

B43 (anti-CD19)-genistein immunoconjugate targets genistein, a naturally occurring protein tyrosine kinase-inhibitory isoflavone to the membrane-associated antiapoptotic CD19-LYN complexes and triggers apoptotic cell death. In this preclinical study, the toxicity profiles of B43-genistein as well as unconjugated genistein were evaluated in cynomolgus monkeys. B43-genistein and genistein were administered either as single bolus injections or daily injections for 5-10 consecutive days via the i.v. route to monkeys. Neither genistein nor B43-genistein was toxic to cynomolgus monkeys, and no test article-related histopathological lesions were found in any of the two genistein-treated or five B43-genistein-treated cynomolgus monkeys. B43-genistein showed a favorable pharmacokinetics in monkeys, with a plasma half-life of 10-23 h. Plasma samples from B43-genistein-treated monkeys elicited potent and CD19 antigenspecific antileukemic activity against human CD19+ leukemia cells in vitro. To our knowledge, this is the first preclinical toxicity and pharmacokinetic study of a tyrosine kinase inhibitor-containing immunoconjugate in nonhuman primates.
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PMID:In vivo toxicity and pharmacokinetic features of B43 (anti-CD19)-genistein immunoconjugate in nonhuman primates. 951 66

A novel homology model of the kinase domain of Janus kinase (JAK) 3 was used for the structure-based design of dimethoxyquinazoline compounds with potent and specific inhibitory activity against JAK3. The active site of JAK3 in this homology model measures roughly 8 A x 11 A x 20 A, with a volume of approximately 530 A3 available for inhibitor binding. Modeling studies indicated that 4-(phenyl)-amino-6,7-dimethoxyquinazoline (parent compound WHI-258) would likely fit into the catalytic site of JAK3 and that derivatives of this compound that contain an OH group at the 4' position of the phenyl ring would more strongly bind to JAK3 because of added interactions with Asp-967, a key residue in the catalytic site of JAK3. These predictions were consistent with docking studies indicating that compounds containing a 4'-OH group, WHI-P131 [4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline], WHI-P154 [4-(3'-bromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline], and WHI-P97 [4-(3',5'-dibromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazolin e], were likely to bind favorably to JAK3, with estimated K(i)s ranging from 0.6 to 2.3 microM. These compounds inhibited JAK3 in immune complex kinase assays in a dose-dependent fashion. In contrast, compounds lacking the 4'-OH group, WHI-P79 [4-(3'-bromophenyl)-amino-6,7-dimethoxyquinazoline], WHI-P111 [4-(3'-bromo-4'-methylphenyl)-amino-6,7-dimethoxyquinazoline], WHI-P112 [4-(2',5'-dibromophenyl)-amino-6,7-dimethoxyquinazoline], WHI-P132 [4-(2'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline], and WHI-P258 [4-(phenyl)-amino-6,7-dimethoxyquinazoline], were predicted to bind less strongly, with estimated K(i)s ranging from 28 to 72 microM. These compounds did not show any significant JAK3 inhibition in kinase assays. Furthermore, the lead dimethoxyquinazoline compound, WHI-P131, which showed potent JAK3-inhibitory activity (IC50 of 78 microM), did not inhibit JAK1 and JAK2, the ZAP/SYK family tyrosine kinase SYK, the TEC family tyrosine kinase BTK, the SRC family tyrosine kinase LYN, or the receptor family tyrosine kinase insulin receptor kinase, even at concentrations as high as 350 microM. WHI-P131 induced apoptosis in JAK3-expressing human leukemia cell lines NALM-6 and LC1;19 but not in melanoma (M24-MET) or squamous carcinoma (SQ20B) cells. Leukemia cells were not killed by dimethoxyquinazoline compounds that were inactive against JAK3. WHI-P131 inhibited the clonogenic growth of JAK3-positive leukemia cell lines DAUDI, RAMOS, LC1;19, NALM-6, MOLT-3, and HL-60 (but not JAK3-negative BT-20 breast cancer, M24-MET melanoma, or SQ20B squamous carcinoma cell lines) in a concentration-dependent fashion. Potent and specific inhibitors of JAK3 such as WHI-P131 may provide the basis for the design of new treatment strategies against acute lymphoblastic leukemia, the most common form of childhood cancer.
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PMID:Structure-based design of specific inhibitors of Janus kinase 3 as apoptosis-inducing antileukemic agents. 1038 46

Recently identified agents that interact with cytoskeletal elements such as tubulin include synthetic spiroketal pyrans (SPIKET) and monotetrahydrofuran compounds (COBRA compounds). SPIKET compounds target the spongistatin binding site of beta-tubulin and COBRA compounds target a unique binding cavity on alpha-tubulin. At nanomolar concentrations, the SPIKET compound SPIKET-P causes tubulin depolymerization and exhibits potent cytotoxic activity against cancer cells. COBRA-1 inhibits GTP-induced tubulin polymerization. Treatment of human breast cancer and brain tumor cells with COBRA-1 caused destruction of microtubule organization and apoptosis. Other studies have identified some promising protein tyrosine kinase inhibitors as anti-cancer agents. These include EGFR inhibitors such as the quinazoline derivative WHI-P97 and the leflunomide metabolite analog LFM-A12. Both LFM-A12 and WHI-P97 inhibit the in vitro invasiveness of EGFR positive human breast cancer cells at micromolar concentrations and induce apoptotic cell death. Dimethoxyquinazoline compounds WHI-P131 and WHI-P154 inhibit tyrosine kinase JAK3 in leukemia cells. Of particular interest is WHI-P131, which inhibits JAK3 but not JAK1, JAK2, SYK, BTK, LYN, or IRK at concentrations as high as 350 microM. Studies of BTK inhibitors showed that the leflunomide metabolite analog LFM-A13 inhibited BTK in leukemia and lymphoma cells. Consistent with the anti-apoptotic function of BTK, treatment of leukemic cells with LFM-A13 enhanced their sensitivity to chemotherapy-induced apoptosis.
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PMID:Structure-based design of novel anticancer agents. 1218 92

Cancer subtype diagnosis using microarray signatures has the potential to transform pathological diagnosis but the routine measurement of genes signatures remains difficult. Reverse transcription polymerase chain reaction (RT-PCR) measurement of Indicator genes for acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) was used to determine gene signatures. Bone marrow (BM) mononuclear cells were sorted into total, CD34(+) and CD34(-) fractions, and mRNAs globally amplified from each fraction using polyA PCR. The expression profile of the 17 top-ranked genes distinguishing AML and ALL were measured by RT-PCR in five ALL, 26 AML, 12 AML remission, four chronic myeloid leukaemia (CML) and nine morphologically normal BM samples. All but two of the genes measured showed similar expression in AML and ALL to that reported previously. Specifically, c-MYB (P </= 0.04) was significantly increased in ALL in the total fraction, whilst HOXA9 (P </= 0.19) and cystatin c (P </= 0.01) were increased in AML in the CD34(+) and CD34(-) fractions, respectively. c-MYB, hSNF2, RBAP48, HKRT-1, LYN, CD33, Adipsin and HOXA9 were increased in AML compared with remission AML, indicating an ability to determine disease activity. The method used is simple, sensitive and robust, enabling routine clinical use, and it can also be extended to other tumours types with gene signatures.
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PMID:Routine expression profiling of microarray gene signatures in acute leukaemia by real-time PCR of human bone marrow. 1602 52

Adult T-cell leukemia/lymphoma (ATL) is an aggressive and fatal disease. We have examined 32 patients with smoldering, chronic, lymphoma and acute leukemia using Affymetrix HG-U133A2.0 arrays. Using the BRB array program, we identified genes differentially expressed in leukemia cells compared with normal lymphocytes. Several unique genes were identified that were overexpressed in leukemic cells, including TNFSF11, RGS13, MAFb, CSPG2, C/EBP-alpha, and TCF4; 200 of the most highly overexpressed ATL genes were analyzed by the Pathway Studio, version 4.0 program. ATL leukemia cells were characterized by an increase in genes linked to "central" genes CDC2/cyclin B1, SYK/LYN, proliferating cell nuclear antigen, and BIRC5. Because of its potential therapeutic importance, we focused our studies on the regulation and function of BIRC5, whose expression was increased in 13 of 14 leukemia samples. TCF4 reporter assays and transfection of DN-TCF4 demonstrated that TCF4 regulates BIRC5 gene expression. Functionally, transfection of ATL cells with BIRC5 shRNA decreased BIRC5 expression and cell viability 80%. Clinical treatment of ATL patients with Zenapax or bortezomib decreased BIRC5 expression and cell viability. These experiments represent the first direct experimental evidence that BIRC5 plays an important role in ATL cell viability and provides important insight into ATL genesis and potential targeted therapies.
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PMID:Gene expression profiling of ATL patients: compilation of disease-related genes and evidence for TCF4 involvement in BIRC5 gene expression and cell viability. 1913 53

Targeted therapy has vastly improved outcomes in certain types of cancer. Extension of this paradigm across a broad spectrum of malignancies will require an efficient method to determine the molecular vulnerabilities of cancerous cells. Improvements in sequencing technology will soon enable high-throughput sequencing of entire genomes of cancer patients; however, determining the relevance of identified sequence variants will require complementary functional analyses. Here, we report an RNAi-assisted protein target identification (RAPID) technology that individually assesses targeting of each member of the tyrosine kinase gene family. We demonstrate that RAPID screening of primary leukemia cells from 30 patients identifies targets that are critical to survival of the malignant cells from 10 of these individuals. We identify known, activating mutations in JAK2 and K-RAS, as well as patient-specific sensitivity to down-regulation of FLT1, CSF1R, PDGFR, ROR1, EPHA4/5, JAK1/3, LMTK3, LYN, FYN, PTK2B, and N-RAS. We also describe a previously undescribed, somatic, activating mutation in the thrombopoietin receptor that is sensitive to down-stream pharmacologic inhibition. Hence, the RAPID technique can quickly identify molecular vulnerabilities in malignant cells. Combination of this technique with whole-genome sequencing will represent an ideal tool for oncogenic target identification such that specific therapies can be matched with individual patients.
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PMID:RNAi screen for rapid therapeutic target identification in leukemia patients. 1943 5

Although activation of the B-cell receptor (BCR) signaling pathway is implicated in the pathogenesis of chronic lymphocytic leukemia (CLL), its clinical impact and the molecular correlates of such response are not clearly defined. T-cell leukemia 1 (TCL1), the AKT modulator and proto-oncogene, is differentially expressed in CLL and linked to its pathogenesis based on CD5(+) B-cell expansions arising in TCL1-transgenic mice. We studied here the association of TCL1 levels and its intracellular dynamics with the in vitro responses to BCR stimulation in 70 CLL cases. The growth kinetics after BCR engagement correlated strongly with the degree and timing of induced AKT phospho-activation. This signaling intensity was best predicted by TCL1 levels and the kinetics of TCL1-AKT corecruitment to BCR membrane activation complexes, which further included the kinases LYN, SYK, ZAP70, and PKC. High TCL1 levels were also strongly associated with aggressive disease features, such as advanced clinical stage, higher white blood cell counts, and shorter lymphocyte doubling time. Higher TCL1 levels independently predicted an inferior clinical outcome (ie, shorter progression-free survival, P < .001), regardless of therapy regimen, especially for ZAP70(+) tumors. We propose TCL1 as a marker of the BCR-responsive CLL subset identifying poor prognostic cases where targeting BCR-associated kinases may be therapeutically useful.
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PMID:High TCL1 levels are a marker of B-cell receptor pathway responsiveness and adverse outcome in chronic lymphocytic leukemia. 1977 Mar 58


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