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)

Signal transducers and activators of transcription (STATs) are a family proteins that mediate cytokine and growth factor-induced signals playing a role in cell differentiation, proliferation, angiogenesis, and apoptosis. One STAT family member, STAT5, is often constitutively active in myeloid leukaemia. Agents that can suppress STAT5 activation have potential for prevention and treatment of cancer. N'-(11H-indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1,2-dia-mine (IQDMA), an indoloquinoline derivative, synthesized in our laboratory, has been demonstrated to be an effective anti-tumor agent in human leukemia cells. In the present report, we tested IQDMA for its ability to suppress STAT5 activation. We found that IQDMA inhibited constitutive activation of STAT5 in HL-60 cells in a dose- and time-dependent manner. The activation of Src and interleukin-6 (IL-6), implicated in STAT5 activation, was also inhibited by the IQDMA. Furthermore, IQDMA up-regulated Bax, and down-regulated Bcl-2, Bcl-X(L), cyclin D1, and vascular endothelial growth factor (VEGF) as followed by growth arrest of HL-60 cells, but the expression of survivin did not change in the presence of IQDMA. Taken together, these results indicate that IQDMA causes significant induction of apoptosis in HL-60 cells via down-regulation of Src, IL-6, and STAT5 signaling and modulation of Bcl-2 family, cyclin D1 and VEGF proteins. Thus, IQDMA appears to be a potential therapeutic agent for treating leukaemia HL-60 cells.
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PMID:Novel indoloquinoline derivative, IQDMA, suppresses STAT5 phosphorylation and induces apoptosis in HL-60 cells. 1863 62

Janus kinase 2 (JAK2)V617F-activating mutations (JAK2mu) occur in myeloproliferative disorders (MPDs) and myelodysplastic syndromes (MDSs). Cell lines MB-02, MUTZ-8, SET-2 and UKE-1 carry JAK2V617F and derive from patients with MPD/MDS histories. Challenging the consensus that expression of JAK2V617F is the sole precondition for cytokine independence in class I cytokine receptor-positive cells, two of four of the JAK2mu cell lines were growth factor-dependent. These cell lines resembled JAK2wt cells regarding JAK2/STAT5 activation: cytokine deprivation effected dephosphorylation, whereas erythropoetin or granulocyte colony-stimulating factor induced phosphorylation of JAK2 and STAT5. Cytokine independence correlated with low expression and cytokine dependence with high expression of the JAK/STAT pathway inhibitor suppressor of cytokine signaling 2 (SOCS2) suggesting a two-step mechanism for cytokine independence of MPD cells: (i) activation of the oncogene JAK2V617F and (ii) inactivation of the tumor suppressor gene SOCS2. Confirming that SOCS2 operates as a negative JAK2V617F regulator, SOCS2 knockdown induced constitutive STAT5 phosphorylation in JAK2mu cells. CpG island hypermethylation is reported to promote SOCS gene silencing in malignant diseases. Accordingly, in one of two cytokine-independent cell lines and in two of seven MPD patients, we found SOCS2 hypermethylation associated with reduced promoter access to transcription factors. Our results provide solid evidence that SOCS2 epigenetic downregulation might be an important second step in the genesis of cytokine-independent MPD clones.
Leukemia 2008 Dec
PMID:SOCS2: inhibitor of JAK2V617F-mediated signal transduction. 1876 47

Chronic myeloid leukemia (CML) represents the first human malignancy successfully treated with a tyrosine kinase inhibitor (TKI; imatinib). However, early relapses and the emergence of imatinib-resistant disease are problematic. Evidence suggests that imatinib and other inhibitors may not effectively eradicate leukemic stem/progenitor cells, and that combination therapy directed to complimentary targets may improve treatment. Abelson helper integration site 1 (Ahi-1)/AHI-1 is a novel oncogene that is highly deregulated in CML stem/progenitor cells where levels of BCR-ABL transcripts are also elevated. Here, we demonstrate that overexpression of Ahi-1/AHI-1 in murine and human hematopoietic cells confer growth advantages in vitro and induce leukemia in vivo, enhancing effects of BCR-ABL. Conversely, RNAi-mediated suppression of AHI-1 in BCR-ABL-transduced lin(-)CD34(+) human cord blood cells and primary CML stem/progenitor cells reduces their growth autonomy in vitro. Interestingly, coexpression of Ahi-1 in BCR-ABL-inducible cells reverses growth deficiencies exhibited by BCR-ABL down-regulation and is associated with sustained phosphorylation of BCR-ABL and enhanced activation of JAK2-STAT5. Moreover, we identified an AHI-1-BCR-ABL-JAK2 interaction complex and found that modulation of AHI-1 expression regulates phosphorylation of BCR-ABL and JAK2-STAT5 in CML cells. Importantly, this complex mediates TKI response/resistance of CML stem/progenitor cells. These studies implicate AHI-1 as a potential therapeutic target downstream of BCR-ABL in CML.
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PMID:AHI-1 interacts with BCR-ABL and modulates BCR-ABL transforming activity and imatinib response of CML stem/progenitor cells. 1893 34

Dasatinib has been reported to potently inhibit juxtamembrane domain mutant KIT(D816V) autophosphorylation and KIT-dependent activation of down stream signaling important for cell growth and survival of neoplastic cells. Additionally, dasatinib induced apoptosis in mast cell and leukemia cell lines expressing KIT(D816V). Here, we present the first case report of long-term hematologic and molecular remission achieved with combined treatment with chemotherapy and dasatinib in a patient with systemic mastocytosis (SM) and acute myeloid leukemia (AML) with mutant KIT(D816V) expression. A 50-year-old male presented with pancytopenia, organomegaly, lymphadenopathy, and lytic bone lesions in the pelvis. The patient was found to have systemic mastocytosis (SM) and acute myelogeneous leukemia (AML) positive for KIT(D816V) and therefore diagnosed with SM with an associated clonal hematological non-mast cell lineage disease (SM-AHNMD). Both primary CD34+ cells containing myeloblasts and CD34- cells containing mastocytes obtained from the diagnostic BM lost viability markedly by in vitro dasatinib treatment. In addition, dasatinib diminished activity of STAT5, STAT3, AKT and ERK and attenuated the levels of c-KIT. The patient achieved a hematologic complete remission (HCR) by two induction chemotherapies with residual mastocytes. Dasatinib (70mg PO bid, days 1-4) was added to consolidation treatments composed of four cycles of high dose cytarabine and was then continued as maintenance therapy (50mg PO bid). Periodic bone marrow (BM) aspirate/biopsies (eight over 18 months) were performed. The patient remained in HCR, and the mastocyte burden decreased by 50%. The bone lytic lesions improved. The KIT(D816V)mutation progressively decreased and became undetectable in the last three BM analyses. This result was confirmed by an independent laboratory showing a lack of c-KIT mutation in both CD34+ cells and CD34- cells in the last BM. No significant adverse effects of dasatinib occurred. Dasatinib has in vitro and in vivo efficacy in SM-AML patients with KIT(D816V) mutation. Along with chemotherapy, dasatinib should be considered in these patients particularly if they cannot undergo allogeneic stem cell transplantation for this poor prognostic AML.
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PMID:Chemotherapy and dasatinib induce long-term hematologic and molecular remission in systemic mastocytosis with acute myeloid leukemia with KIT D816V. 1898 3

Pre-B-cell leukemia spontaneously develops in BLNK-deficient mice, and pre-B-cell acute lymphoblastic leukemia cells in children often lack BLNK protein expression, demonstrating that BLNK functions as a tumor suppressor. However, the mechanism by which BLNK suppresses pre-B-cell leukemia, as well as the identification of other genetic alterations that collaborate with BLNK deficiency to cause leukemogenesis, are still unknown. Here, we demonstrate that the JAK3/STAT5 signaling pathway is constitutively activated in pre-B leukemia cells derived from BLNK(-/-) mice, mostly due to autocrine production of IL-7. Inhibition of IL-7R signaling or JAK3/STAT5 activity resulted in the induction of p27(kip1) expression and cell-cycle arrest, accompanied by apoptosis in the leukemia cells. Transgene-derived constitutively active STAT5 (STAT5b-CA) strongly synergized with the loss of BLNK to initiate leukemia in vivo. In the leukemia cells, exogenously expressed BLNK inhibited autocrine JAK3/STAT5 signaling, resulting in p27(kip1) induction, cell-cycle arrest, and apoptosis. BLNK-inhibition of JAK3 was dependent on the binding of BLNK to JAK3. These data indicate that BLNK normally regulates IL-7-dependent proliferation and survival of pre-B cells through direct inhibition of JAK3. Thus, somatic loss of BLNK and concomitant mutations leading to constitutive activation of Jak/STAT5 pathway result in the generation of pre-B-cell leukemia.
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PMID:BLNK suppresses pre-B-cell leukemogenesis through inhibition of JAK3. 1904 79

N'-(11H-indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1,2-diamine (IQDMA), an indoloquinoline derivative, synthesized in our laboratory, has been demonstrated to be an effective antitumor agent in human leukemia cells. In the present study, treatment with IQDMA inhibited phosphorylation of epidermal growth factor receptor (EGFR), Src, Bcr-Abl, and Janus-activated kinase (JAK2) in a time-dependent manner. IQDMA also degraded JAK2 protein. Moreover, signal transducer and activator of transcription 5 (STAT5) signaling were also blocked by IQDMA. However, IQDMA did not inhibit other oncogenic and tumor survival pathways such as those mediated by Akt and extracellular signal-regulated kinase 1/2. Furthermore, IQDMA upregulated the expression of p21 and p27 and downregulated the expression of cyclin D1, myeloid cell leukemia-1(Mcl-1), Bcl-X(L), and vascular endothelial growth factor (VEGF). Taken together, these results indicate that IQDMA causes significant induction of apoptosis in K562 cells via downregulation of EGFR, Src, Bcr-Abl, JAK2, and STAT5 signaling and modulation of p21, p27, cyclin D1, Mcl-1, Bcl-X(L), and VEGF proteins. Thus, IQDMA appears to be a potential therapeutic agent for treating leukemia K562 cells.
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PMID:Novel indoloquinoline derivative, IQDMA, inhibits STAT5 signaling associated with apoptosis in K562 cells. 1911 Oct 1

Focal adhesion kinase (FAK) is constitutively activated and tyrosine phosphorylated in BCR/ABL-transformed hematopoietic cells, but the role it plays during leukemogenesis remains unclear. Here, we examined the effects of RNA interference-mediated FAK silencing on leukemogenesis induced by a BCR/ABL-transformed cell line. Transduction of BCR/ABL-BaF3 cells with FAK shRNA inhibited FAK expression and reduced STAT5 phosphorylation, but induced caspase-3 activation. In vitro studies showed that treatment with FAK shRNA resulted in impaired cell proliferation and colony formation, while increasing cell apoptosis. Mice that received transplants of BCR/ABL-BaF3 cells with FAK shRNA displayed significantly prolonged survival time and diminished leukemia progression. In addition, FAK silencing enhanced in vitro and in vivo efficacy of ABL tyrosine kinase inhibitor imatinib in BCR/ABL-BaF3 cells. Our results suggest that FAK is critical for leukemogenesis and might be a potential target for leukemia therapy.
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PMID:FAK silencing inhibits leukemogenesis in BCR/ABL-transformed hematopoietic cells. 1935 1

Current methods of protein detection are insensitive to detecting subtle changes in oncoprotein activation that underlie key cancer signaling processes. The requirement for large numbers of cells precludes serial tumor sampling for assessing a response to therapeutics. Therefore, we have developed a nanofluidic proteomic immunoassay (NIA) to quantify total and low-abundance protein isoforms in nanoliter volumes. Our method can quantify amounts of MYC oncoprotein and B cell lymphoma protein-2 (BCL2) in Burkitt's and follicular lymphoma; identify changes in activation of extracellular signal-related kinases-1 (ERK1) and ERK2, mitogen-activated kinase-1 (MEK), signal transducer and activator of transcription protein-3 (STAT3) and STAT5, c-Jun N-terminal kinase (JNK) and caspase-3 in imatinib-treated chronic myelogeneous leukemia (CML) cells; measure an unanticipated change in the phosphorylation of an ERK2 isomer in individuals with CML who responded to imatinib; and detect a decrease in STAT3 and STAT5 phosphorylation in individuals with lymphoma who were treated with atorvastatin. Therefore, we have described a new and highly sensitive method for determining oncoprotein expression and phosphorylation in clinical specimens for the development of new therapeutics for cancer.
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PMID:Nanofluidic proteomic assay for serial analysis of oncoprotein activation in clinical specimens. 1979 63

KW-2449, a multikinase inhibitor of FLT3, ABL, ABL-T315I, and Aurora kinase, is under investigation to treat leukemia patients. In this study, we examined its possible modes of action for antileukemic effects on FLT3-activated, FLT3 wild-type, or imatinib-resistant leukemia cells. KW-2449 showed the potent growth inhibitory effects on leukemia cells with FLT3 mutations by inhibition of the FLT3 kinase, resulting in the down-regulation of phosphorylated-FLT3/STAT5, G(1) arrest, and apoptosis. Oral administration of KW-2449 showed dose-dependent and significant tumor growth inhibition in FLT3-mutated xenograft model with minimum bone marrow suppression. In FLT3 wild-type human leukemia, it induced the reduction of phosphorylated histone H3, G(2)/M arrest, and apoptosis. In imatinib-resistant leukemia, KW-2449 contributed to release of the resistance by the simultaneous down-regulation of BCR/ABL and Aurora kinases. Furthermore, the antiproliferative activity of KW-2449 was confirmed in primary samples from AML and imatinib-resistant patients. The inhibitory activity of KW-2449 is not affected by the presence of human plasma protein, such as alpha1-acid glycoprotein. These results indicate KW-2449 has potent growth inhibitory activity against various types of leukemia by several mechanisms of action. Our studies indicate KW-2449 has significant activity and warrants clinical study in leukemia patients with FLT3 mutations as well as imatinib-resistant mutations.
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PMID:KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. 1954 23

Mixed-lineage-leukemia (MLL) fusion oncogenes are closely involved in infant acute leukemia, which is frequently accompanied by mutations or overexpression of FMS-like receptor tyrosine kinase 3 (FLT3). Earlier studies have shown that MLL fusion proteins induced acute leukemia together with another mutation, such as an FLT3 mutant, in mouse models. However, little has hitherto been elucidated regarding the molecular mechanism of the cooperativity in leukemogenesis. Using murine model systems of the MLL-fusion-mediated leukemogenesis leading to oncogenic transformation in vitro and acute leukemia in vivo, this study characterized the molecular network in the cooperative leukemogenesis. This research revealed that MLL fusion proteins cooperated with activation of Ras in vivo, which was substitutable for Raf in vitro, synergistically, but not with activation of signal transducer and activator of transcription 5 (STAT5), to induce acute leukemia in vivo as well as oncogenic transformation in vitro. Furthermore, Hoxa9, one of the MLL-targeted critical molecules, and activation of Ras in vivo, which was replaceable with Raf in vitro, were identified as fundamental components sufficient for mimicking MLL-fusion-mediated leukemogenesis. These findings suggest that the molecular crosstalk between aberrant expression of Hox molecule(s) and activated Raf may have a key role in the MLL-fusion-mediated-leukemogenesis, and may thus help develop the novel molecularly targeted therapy against MLL-related leukemia.
Leukemia 2009 Dec
PMID:Mixed-lineage-leukemia (MLL) fusion protein collaborates with Ras to induce acute leukemia through aberrant Hox expression and Raf activation. 1971 Jun 96


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