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)

In an effort to identify unique tyrosine kinases found in human leukemia cell lines, we utilized polymerase chain reaction (PCR) technology and degenerate oligonucleotide primers to produce a cDNA library of kinase catalytic domains found in the human monocytic cell line AML-193. This search yielded a member of the class 3 tyrosine kinases closely related to the murine kinase FD-22. Previous work has identified this kinase as JAK1. This class of tyrosine kinases is characterized by being ubiquitously expressed, lacking both a ligand-binding domain and a SH2 domain, while containing a second domain similar to a degenerate kinase domain. Our studies focused on the further characterization of this class 3 tyrosine kinase using Northern blot analysis to demonstrate an increase in steady-state mRNA by interferon-gamma in human monocytes. A human-hamster somatic cell hybrid panel and linkage mapping was used to assign JAK1 (aml-116) to human chromosome 1.
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PMID:Characterization of a class 3 tyrosine kinase. 137 77

Oncostatin M (OSM) is a 28-kD glycoprotein recently identified as a growth factor for human multiple myeloma cells. It belongs to a family of distantly related cytokines that includes interleukin 6, ciliary neurotrophic factor, leukemia-inhibitory factor, and interleukin 11. These cytokines initiate signaling by inducing either homodimerization of gp130 or heterodimerization of gp130 with leukemia-inhibitory factor receptor beta components. Such dimerization in turn activates receptor-associated tyrosine kinases. In the present study using U266B1 human multiple myeloma cells, we show that OSM induces tyrosine phosphorylation and activation of JAK2, but not JAK1 or Tyk2, kinases. The results also demonstrate that OSM induces direct interaction of JAK2 kinase with Grb2, an SH2/SH3 domain containing adaptor protein. The SH2 domain of Grb2 is directly associated with tyrosine-phosphorylated JAK2. Furthermore, the presence of Sos in the JAK2-Grb2 complex suggests a role for Ras in OSM-transduced signaling.
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PMID:Oncostatin M induces association of Grb2 with Janus kinase JAK2 in multiple myeloma cells. 750 25

Bcr/Abl is a chimeric oncogene that can cause both acute and chronic human leukemias. Bcr/Abl-encoded proteins exhibit elevated kinase activity compared to c-Abl, but the mechanisms of transformation are largely unknown. Some of the biological effects of Bcr/Abl overlap with those of hematopoietic cytokines, particularly interleukin 3 (IL-3). Such effects include mitogenesis, enhanced survival, and enhanced basophilic differentiation. Therefore, it has been suggested that p210Bcr/Abl and the IL-3 receptor may activate some common signal transduction pathways. An important pathway for IL-3 signaling involves activation of the Janus family kinases (JAKs) and subsequent tyrosyl phosphorylation of STAT proteins (signal transducers and activators of transcription). This pathway directly links growth factor receptors to gene transcription. We analyzed JAK activation, STAT protein phosphorylation, and the formation of specific DNA-binding complexes containing STAT proteins, in a series of leukemia cell lines transformed by Bcr/Abl or other oncogenes. We also examined these events in cell lines transformed by a temperature sensitive (ts) mutant of Bcr/Abl, where the kinase activity of Abl could be regulated. STAT1 and STAT5 were found to be constitutively phosphorylated in 32D, Ba/F3, and TF-1 cells transformed by Bcr/Abl, but not in the untransformed parental cell lines in the absence of IL-3. Phosphorylation of STAT1 and STAT5 was also observed in the human leukemia cell lines K562 and BV173, which express the Bcr/Abl oncogene, but not in several Bcr/Abl-negative leukemia cell lines. Phosphorylation of STAT1 and STAT5 was directly due to the tyrosine kinase activity of Bcr/Abl since it could be activated or deactivated by temperature shifting of cells expressing the Bcr/Abl ts mutant. DNA-STAT complexes were detected in all Bcr/Abl-transformed cell lines and they were supershifted by antibodies against STAT1 and STAT5. DNA-STAT complexes in 32Dp210Bcr/Abl cells were similar, but not identical, to those formed after IL-3 stimulation. It is interesting to note that JAK kinases (JAK1, JAK2, JAK3, and Tyk2) were not consistently activated in Bcr/Abl-positive cells. These data suggest that STATs can be activated directly by Bcr/Abl, possibly bypassing JAK family kinase activation. Overall, our results suggest a novel mechanism that could contribute to some of the major biological effects of Bcr/Abl transformation.
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PMID:Tyrosyl phosphorylation and DNA binding activity of signal transducers and activators of transcription (STAT) proteins in hematopoietic cell lines transformed by Bcr/Abl. 864 85

Interleukin-7 (IL-7) stimulates the proliferation of normal and leukemic B and T cell precursors and T lymphocytes. Activation of the JAK/STAT pathway has been implicated in IL-7R signaling. We investigated which STAT complexes are formed upon stimulation of B cell precursor acute lymphoblastic leukemia (BCP-ALL) cells with IL-7. Gel retardation assays with STAT-binding oligonucleotides showed that IL-7 induces the formation of two major STAT complexes in BCP-ALL cells. Supershifts with anti-STAT antibodies identified these as STAT1 and STAT5 complexes. This pattern of STAT activation was seen in all BCP-ALL cases that respond to IL-7 in proliferation assays. IL-7 also induced STAT/DNA binding in BCP-ALL cases that failed to proliferate in response to IL-7, suggesting that the ability of IL-7R to activate the JAK/STAT pathway per se is not sufficient for proliferation induction. To determine the contribution of the cytoplasmic domain of the IL-7 receptor alpha chain (IL-7R alpha) to activation of STAT proteins, transfectants of the murine pro-B cell line BAF3 were made that express chimeric receptors consisting of the extracellular domain of human granulocyte colony-stimulating factor receptor (G-CSF-R) and the transmembrane and intracellular domains of human IL-7R alpha. Activation of the chimeric G-CSF-R/IL-7R alpha with G-CSF resulted in a full proliferative response and induced the phosphorylation of JAK1 but not JAK2. Major STAT complexes activated by G-CSF-R/IL-7R alpha contained STAT1 or STAT5, while some formation of STAT3-containing complexes was also seen. These findings establish that STAT1 and STAT5, and possibly STAT3, are activated upon stimulation of precursor B cells with IL-7. The data further indicate that the IL-7R alpha chains are directly involved in the activation of JAKs and STATs and have a major role in proliferative signaling in precursor B cells.
Leukemia 1996 Aug
PMID:Interleukin-7 signaling in human B cell precursor acute lymphoblastic leukemia cells and murine BAF3 cells involves activation of STAT1 and STAT5 mediated via the interleukin-7 receptor alpha chain. 870 37

Friend leukemia virus complex (FLV) consists of replication-defective, Friend spleen focus-forming virus (F-SFFV) and replication-competent, Friend murine leukemia virus (F-MuLV). We produced transgenic mice possessing F-SFFV gp55 gene and clarified that the gp55 glycoprotein encoded by F-SFFV env-related gene is, by itself, responsible for the initiation of erythroleukemia. The occurrence of erythroleukemia, however, is sporadic in these mice. Erythroleukemia cell lines established from these mice possessed mutations in the p53 allele. One had a temperature-sensitive mutant p53 allele, p53Val-135 and showed induction of apoptosis by expressing a wild-type p53 protein at 32 degrees C. Superinfection of the mice with Moloney murine leukemia virus (Mo-MuLV) conferred 100% induction of erythroleukemia, mutating p53 gene or activating Spfi-1 gene by insertional events. Activation of the JAK/STAT pathway, which is involved in cytokine signaling, was investigated in the gp55 signaling mediated by the erythropoietin receptor. JAK1 and STAT5 were constitutively tyrosine-phosphorylated but the DNA binding activity of STAT5 was not induced.
Leukemia 1997 Apr
PMID:Pathogenesis of Friend leukemia virus. 920 27

Friend spleen focus forming-virus (F-SFFV) induces acute erythroleukemia in susceptible mice. Initiation of the erythroleukemia is due to binding of the env-related glycoprotein gp55 encoded by F-SFFV to the erythropoietin receptor (EPOR). The gp55/EPOR interaction induces prolonged and growth factor independent proliferation in a factor-dependent cell line. In erythropoietin (EPO) signaling, the JAK2/STAT5 pathway was shown to be activated downstream of the EPOR to transmit the signal to the cells. To determine members of the JAK family and the STAT transcription factor family involved in the gp55/EPOR signaling, we examined tyrosine phosphorylation of JAKs and STATs in F-SFFV-infected erythroid or erythroleukemic cells. JAK1 and STAT5 were constitutively tyrosine-phosphorylated but the DNA binding activity of STAT5 was not induced without EPO stimulation in erythroblastoid cells from spleens of F-SFFV-infected mice and erythroleukemia cell lines derived from gp55-transgenic mice. These results indicate that JAK1 is involved in the gp55/EPOR signaling but STAT5 is not playing an essential role in the growth of those erythroid cells.
Leukemia 1997 Apr
PMID:Activation of the JAK1-STAT5 pathway by binding of the Friend virus gp55 glycoprotein to the erythropoietin receptor. 920 15

Downregulation of bcr-abl expression in the chronic myelogenous leukemia cell line K562 using antisense oligonucleotides has been shown to enhance the sensitivity of the cells to apoptotic stimuli, suggesting that p210 bcr-abl, like bcl-2 functions as an anti-apoptosis factor (McGahon A et al, Blood 1994, 83: 1179). In these experiments, the inhibition of p210 bcr-abl expression alone was not sufficient to induce apoptosis. We demonstrated that exposure to low doses (0.5 mM) of a butyric acid analog, arginine butyrate, was capable of inducing apoptosis in selected leukemia cell lines, including K562 cells, and in fresh leukemia cells from patients with chronic myelogenous leukemia. To further explore the mechanisms of this effect, we examined expression of p210 bcr-abl after butyrate exposure and found a dose-related inhibition of p210 bcr-abl protein without concordant change in other phosphoproteins, including the JAK-1 kinase. Further analysis revealed that the inhibition of bcr-abl expression occurs due to transcriptional regulation of the bcr-abl gene by arginine butyrate. These results suggest that arginine butyrate and other butyrate analogs alone or in combination may be useful in the therapy of patients with chronic myelogenous leukemia or bcr-abl expressing acute leukemias.
Leukemia 1998 Jun
PMID:Arginine butyrate downregulates p210 bcr-abl expression and induces apoptosis in chronic myelogenous leukemia cells. 963 22

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

The Janus kinase family of proteins, with four mammalian members (JAK1, JAK2, JAK3 and TYK2), plays an essential role in the signal transduction pathway from non-catalytic cytokine receptors to the nucleus. We recently reported the involvement of ETV6-JAK2 fusion genes in the development of leukemia of both lymphoid and myeloid origin. Dominant missense mutations of hopscotch, a Drosophila JAK homologue, causing leukemia-like defects were described. One of these mutations affected a conserved residue of the kinase- like JH2 domain and the introduction of this mutation in murine Jak2 resulted in the constitutional activation of its kinase activity. In order to further analyze its role in leukemogenesis, we cloned human JAK2 and determined its genomic organization. Twenty-four exons spanning a region of approximately 150 kb were identified. A mutation analysis of the exons 13 to 19, encoding the kinase-like JH2 domain failed to detect activating mutations in leukemia samples, suggesting that this is a rare event in human leukemia.
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PMID:Genomic organization of human JAK2 and mutation analysis of its JH2-domain in leukemia. 1044 13

Although dephosphorylation of tyrosine containing proteins is considered a necessary step in the induction of leukemia cell differentiation by hybrid polar compounds (HPC), the crucial actors in this step remain unknown. We present evidence that tyrosine phosphorylation of JAK1 and JAK2 is down-regulated in murine erythroleukemia cells (MELC) within the first 6 h of their exposure to the prototype of the HPC family, hexamethylenebisacetamide (HMBA), with full recovery at 14 h. Further evidence that the JAKs-centered signalling pathway is switched off early by HMBA was provided by the demonstration that STAT5, a downstream member of this pathway, turned out to be completely dephosphorylated at 6 h in HMBA-treated cells. This JAKs dephosphorylation did not occur in HMBA-resistant clones, suggesting that JAKs are possible targets of the dephosphorylative process required for leukemia cell commitment to differentiation. These results may have impact on leukemia therapy based on JAKs inhibitors.
Leukemia 2000 Dec
PMID:A transient dephosphorylation of JAK1 and JAK2 characterises the early-phase response of murine erythroleukemia cells to the differentiation inducer hexamethylenebisacetamide. 1118


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