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)

The oncogenic BCR/ABL protein protects hematopoietic cells from apoptosis induced by growth factor deprivation, but the mechanisms are only partially understood. A BCR/ABL mutant lacking amino acids 176-426 in the BCR domain (p185DeltaBCR) failed to protect interleukin 3-deprived 32Dcl3 myeloid precursor cells from apoptosis, although it possessed tyrosine kinase activity and was capable of activating the Ras-Raf-MAP kinase pathway. Compared to p185 wild-type transfectants, p185DeltaBCR-transfected cells showed markedly reduced levels of Bcl-2 and expressed the hypophosphorylated, proapoptotic form of BAD. Bcl-2 expression in the mitochondrial fraction of p185DeltaBCR cells was also markedly diminished and mitochondrial RAF was undetectable. In p185DeltaBCR cells transfected with a mitochondria-targeted, constitutively active RAF (M-Raf) BAD was expressed in the hyperphosphorylated form and released from the mitochondria into the cytosol. p185DeltaBCR/M-Raf-transfected cells were completely resistant to apoptosis induced by growth factor deprivation in vitro. Moreover, constitutive expression of dominant-negative M-Raf (K375W) enhanced the susceptibility of 32Dcl3 cells expressing wild-type BCR/ABL to apoptosis. In severe combined immunodeficiency (SCID) mice, p185DeltaBCR/M-Raf double transfectants were leukemogenic, whereas cells expressing only p185DeltaBCR showed no leukemogenic potential. Together, these data support the existence of a BCR/ABL-dependent pathway that leads to expression of an active RAF in the mitochondria and promotes antiapoptotic and leukemia-inducing effects of BCR/ABL.
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PMID:Expression of constitutively active Raf-1 in the mitochondria restores antiapoptotic and leukemogenic potential of a transformation-deficient BCR/ABL mutant. 962 59

The expression of Bcl-2 family members was examined in normal and leukemic hematopoietic cells. Immature hematopoietic progenitor cells (CD34+/33-/13-) did not express Bcl-2 but Bcl-XL, the majority of CD34 cells expressed Bcl-2, Bcl-XL and BAD, and normal promyelocytes (CD34-/33+) lacked expression of both Bcl-2 and Bcl-XL, while leukemic CD34+progenitors and promyelocytes expressed these anti-apoptotic proteins. In AML, Bcl-2 expression was higher on CD34+ than on all AML cells, however, expression of Bcl-2 or Bcl-XL did not predict achievement of complete remission. Surprisingly, low Bcl-2 content was associated with poor survival in a group of patients with poor prognosis cytogenetics. The anti-apoptotic BAD protein was found to be expressed in AML, but was phosphorylated in 41/42 samples. Phosphorylation was found at both sites, Ser 112 and Ser 136. During induction chemotherapy, Bcl-2 levels of CD34 cells increased significantly. In the context of evidence for small numbers of leukemic CD34+ cells expressing very high levels of Bcl-2 prior to therapy, this finding is interpreted as a survival advantage of Bcl-2 overexpressing progenitors and rapid elimination of cells with low Bcl-2. Bcl-2 and Bcl-XL were both expressed in minimal residual disease cells. Downregulation of Bcl-2 mRNA and protein was observed by ATRA and the combination of Ara-C, followed by ATRA, resulted in markedly increased cytotoxicity in HL-60 cells, as compared to Ara-C alone or ATRA followed by Ara-C. Implications of these findings for the development of new therapeutic strategies for AML are discussed.
Leukemia 1999 Nov
PMID:Expression of Bcl-2-related genes in normal and AML progenitors: changes induced by chemotherapy and retinoic acid. 1055 66

The majority of ovarian follicles undergo atresia mediated by apoptosis. Bcl-2-related proteins act as regulators of apoptosis via the formation of dimers with proteins inside and outside the Bcl-2 family. Previous studies have identified BAD as a proapoptotic Bcl-2 family member expressed in the ovary. It is known that BAD phosphorylation induced by survival factors leads to its preferential binding to 14-3-3 and suppression of the death-inducing function of BAD. To identify ovarian binding partners for hypophosphorylated BAD, we performed a yeast two-hybrid screening of a rat ovary complementary DNA library using as bait a mutant BAD incapable of binding to 14-3-3. Screening of yeast transformants yielded positive clones encoding the rat ortholog of Mcl-1 (myeloid cell leukemia-1), an antiapoptotic Bcl-2 protein. Amino acid sequence analysis revealed that rat and human Mcl-1 showed a complete conservation of the Bcl-2 homology domains BH1, BH2, and BH3. In the yeast two-hybrid system, Mcl-1 binds to the hypophosphorylated mutant of BAD and interacts preferentially with different proapoptotic (Bax, Bak, Bok, Bik, and BOD) compared with antiapoptotic Bcl-2 family members (Bcl-2, Bcl-xL, Bcl-w, Bfl-1, CED-9, and BHRF-1). Northern blot hybridization demonstrated expression of Mcl-1 transcripts of 2.3 and 3.7 kb in the ovary and diverse other rat tissues. In immature rats, PMSG treatment led to a transient increase in the 2.3-kb Mcl-1 transcript, peaking at 6 h after injection and returning to baseline levels after 24 h. Moreover, the same transcript was induced in the PMSG-primed preovulatory rat ovary 6 h after the administration of ovulatory doses of either hCG or FSH. In situ hybridization studies revealed that the gonadotropin stimulation of ovarian Mcl-1 message occurs in both granulosa and thecal cells. In conclusion, rat Mcl-1 was identified as an ovarian BAD-interacting protein and the message for the antiapoptotic Mcl-1 protein was induced after treatment with gonadotropins in granulosa and thecal cells of growing follicles.
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PMID:Characterization of the antiapoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) and the stimulation of its message by gonadotropins in the rat ovary. 1057 8

Human T lymphotropic virus type I (HTLV-I) is the etiological agent of adult T-cell lymphocytic leukemia (ATLL), whereas HTLV-II has not been associated with hematopoietic malignancies. The control of apoptotic pathways has emerged as a critical step in the development of many cancer types. As a result, the underlying mechanism of long-term survival of HTLV-I and HTLV-II was studied in infected T cells in vitro and in ex vivo ATLL samples. Results indicate that HTLV-I- and HTLV-II-infected T cells in vitro express high levels of the antiapoptotic protein Bcl compared with other human leukemic T cell lines or uninfected peripheral blood mononuclear cells. The levels of proapoptotic proteins Bax, BAD, and Bak were not significantly altered. HTLV-I and HTLV-II viral transactivators, Tax1 and Tax2, are known to increase expression of cellular genes. These proteins were tested for increased transcription from the human Bcl2 and Bcl-X(L) promoters. Whereas no effect was observed on the Bcl2 promoter, both Tax1 and Tax2 increased transcription of the Bcl-X(L) promoter in T cells, although Tax1 appeared to be more efficient than Tax2. The biological significance of these observations was validated by the finding of an increased expression of Bcl-X(L) in ex vivo ATLL cells, especially from patients unresponsive to various chemotherapy regimens. Altogether, these data suggest that overexpression of Bcl-X(L )in vivo( )may be in part responsible for the resistance of ATLL cells to chemotherapy. In addition, inefficient activation of the Bcl-X(L) promoter by Tax2 may result in a shorter survival time of HTLV-II-infected cells in vivo and a diminished risk of leukemia development.
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PMID:Bcl-X(L) is up-regulated by HTLV-I and HTLV-II in vitro and in ex vivo ATLL samples. 1089 62

Growth factor-dependent hematopoietic cell lines expressing the BCR/ABL oncoprotein of the Ph chromosome show growth factor-independent proliferation and resistance to apoptosis. Apoptosis resistance of BCR/ABL-expressing cells may depend on enhanced expression of anti-apoptotic proteins as well as reduced expression and/or inactivation of pro-apoptotic proteins. Compared to myeloid precursor 32Dcl3 cells expressing wild type BCR/ABL, cells expressing a BCR/ABL mutant lacking amino acids 176-426 in the BCR domain (p185 delta BCR) are susceptible to apoptosis induced by interleukin-3 (IL-3) deprivation. These cells exhibited the hypophosphorylated apoptotic BAD and markedly reduced levels of Bcl-2. Upon ectopic expression of Bcl-2, these cells showed no changes in BAD phosphorylation, but they became apoptosis-resistant and proliferated in the absence of IL-3, albeit more slowly than cells expressing wild type BCR/ABL. Moreover, the p185 delta BCR/Bcl-2 double transfectants were leukemogenic when injected into immunodeficient mice, but Bcl-2 expression did not restore the leukemia-inducing effects of p185 delta BCR to the levels of wild type BCR/ABL. Leukemic cells recovered from the spleen of mice injected with p185 delta BCR/Bcl-2 cells did not show rearrangements in the Bcl-2 genomic locus, but they exhibited enhanced proliferation in culture and induced a rapidly fatal disease process when inoculated in secondary recipient mice. Together, these data support the importance of anti-apoptotic pathways for BCR/ABL-dependent leukemogenesis and suggest that Bcl-2 expression promotes secondary changes leading to a more aggressive tumor phenotype. (Blood. 2000;96:3915-3921)
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PMID:Bcl-2 expression restores the leukemogenic potential of a BCR/ABL mutant defective in transformation. 1109 78

Inhibitors of Bcl-2 may be useful therapeutic agents for the treatment of a wide variety of malignancies including leukemia. A potential prototype of such a compound is the endogenous Bcl-2 and Bcl-xL binding protein BAD. Previous reports indicate that BAD can overcome the anti-apoptotic effect of Bcl-xL but not Bcl-2. If BAD cannot induce apoptosis in cells over-expressing Bcl-2, it would limit the application of molecules like BAD as novel anti-tumor agents. We report that transient transfection of BAD induced cell death in cells with and without over-expression of Bcl-2 or Bcl-xL. Forty-eight hours after transfection, BAD increased cell death in COS, COS Bcl-2, and COS Bcl-xL cells as demonstrated by decreased GFP expression, and an increase in the number of number of floating cells. In addition, BAD induced cell death in leukemic cell lines over-expressing Bcl-2 and Bcl-xL as determined by changes in luciferase activity. BAD-induced apoptosis was not accompanied by loss of mitochondrial membrane potential. Therefore, we conclude that transient transfection of BAD directly induces apoptosis in cells over-expressing Bcl-2 or Bcl-xL and validates the pursuit of molecules like BAD as novel therapeutic agents.
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PMID:BAD induces apoptosis in cells over-expressing Bcl-2 or Bcl-xL without loss of mitochondrial membrane potential. 1169 8

Benzamide riboside, a recently discovered inhibitor of IMP dehydrogenase (IMPDH) exhibits oncolytic activity. IMPDH is the key enzyme of de novo guanylate biosynthesis and was shown to be linked with proliferation. Therefore, IMPDH is a very good target for antitumor therapy. In order to be active, benzamide riboside has to be converted to BAD, an NAD analogue that binds to the NAD site on IMPDH. Inhibition of the enzyme by benzamide riboside selectively inhibits tumor cell growth and induces apoptosis in various human tumor cell lines. In this manuscript we describe the induction of the CD71 transferrin receptor in human promyelocytic leukemia HL-60 cells following treatment with benzamide riboside. The results indicate a possible involvement of the iron metabolism in the action of this new compound. Benzamide riboside might be clinically used in the treatment of leukemia and solid tumors, alone or as part of combination therapy. Since transferrin receptors are overexpressed in certain cancers, such as glioma and colon cancer, a combination therapy that includes benzamide riboside in transferrin-coupled liposomes will not only target cancer cells but also leads to suicidal action because benzamide riboside will upregulate transferrin receptors on cancer cells thereby make it accessible to dose-intensive chemotherapy. We therefore believe that benzamide riboside itself or derivatives of benzamide riboside might become an important addition for the treatment to diseases that are otherwise fatal.
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PMID:Benzamide riboside, a recent inhibitor of inosine 5'-monophosphate dehydrogenase induces transferrin receptors in cancer cells. 1196 39

AG957 (NSC 654705) is a tyrphostin tyrosine kinase inhibitor that has been demonstrated previously to induce growth arrest in chronic myelogenous leukemia cells by inhibiting p210(bcr-abl) kinase activity and by stabilizing the association of p210(bcr-abl) kinase with its signaling adaptor molecules, Shc and Grb2. In previous studies, it has been demonstrated that AG957-associated down-regulation of bcr-abl activates the cytochrome c/Apaf-1/caspase-9 pathway and induces apoptosis in chronic myelogenous leukemia blasts and progenitor cells. While AG957 has been purported to have specificity for the p210(bcr-abl) kinase, antiproliferative effects of AG957 in normal T-lymphocytes and bcr-abl negative leukemia cells suggest that other targets, such as c-CBL, may be substrates. In this study, we explored the mechanisms of AG957-mediated growth inhibition and apoptosis in the p210(bcr-abl) negative leukemia cell lines Nalm-6 and Jurkat, and demonstrate that AG957-mediated apoptosis is associated with altered phosphorylation of Akt and BAD, which destabilizes the Bcl-xL/BAD complex and releases the block to apoptosis. We, therefore, propose that AG957 induces apoptosis in bcr-abl negative hematopoietic cells by affecting the phosphorylation state of phosphatidylinositol-3 kinase/Akt.
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PMID:Mechanisms of apoptosis by the tyrphostin AG957 in hematopoietic cells. 1199 36

The phosphatidylinositol 3-kinase (PI3K)/AKT protein kinase pathway is involved in cell growth, proliferation, and apoptosis. The functional activation of PI3K/AKT provides survival signals and blockade of this pathway may facilitate cell death. Downstream targets of PI3K-AKT include the proapoptotic protein BAD, caspase-9, NF-kappaB, and Forkhead. We have previously reported that BAD is constitutively phosphorylated in primary acute myeloid leukemia (AML) cells, a post-transcriptional modification, which inactivates its proapoptotic function. In this study, we tested the hypothesis that the inhibition of PI3K by LY294002 results in the dephosphorylation of AKT and BAD, and thus promote leukemia cell apoptosis. We investigated the effects of LY294002 in megakaryocytic leukemia-derived MO7E cells, primary AML and normal bone marrow progenitor cells. In MO7E cells, LY294002 reduced AKT kinase activity, induced dephosphorylation of AKT and BAD, and increased apoptosis. Concomitant inhibition of mitogen-activated protein kinase signaling or combination with all-trans retinoic acid further enhanced apoptosis of leukemic cells. In primary AML samples, clonogenic cell growth was significantly reduced. Normal hematopoietic progenitors were less affected, suggesting preferential targeting of leukemia cells. In conclusion, the data suggest that the inhibition of the PI3K/AKT signaling pathway restores apoptosis in AML and may be explored as a novel target for molecular therapeutics in AML.
Leukemia 2004 Feb
PMID:Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias. 1462 71

Phosphoinositol-3-kinase (PI3K)/protein kinase B (AKT) and Fms-like tyrosine kinase 3 (FLT3) signaling are aberrantly activated in acute myelogenous leukemia (AML) cells. Constitutively activated AKT and FLT3 regulate leukemia cell survival and resistance to chemotherapy. In this study, we investigated the effects of the novel multiple kinase inhibitor KP372-1 on the survival of AML cell lines and primary AML samples. KP372-1 directly inhibited the kinase activity of AKT, PDK1, and FLT3 in a concentration-dependent manner. Western blot analysis indicated that KP372-1 decreased the phosphorylation of AKT on both Ser(473) and Thr(308); abrogated the phosphorylation of p70S6 kinase, BAD, and Foxo3a via PI3K/AKT signaling; and down-regulated expression of PIM-1 through direct inhibition of FLT3. Treatment of AML cell lines with KP372-1 resulted in rapid generation of reactive oxygen species and stimulation of oxygen consumption, followed by mitochondrial depolarization, caspase activation, and phosphatidylserine externalization. KP372-1 induced pronounced apoptosis in AML cell lines and primary samples irrespective of their FLT3 status, but not in normal CD34(+) cells. Moreover, KP372-1 markedly decreased the colony-forming ability of primary AML samples (IC(50) < 200 nmol/L) with minimal cytotoxic effects on normal progenitor cells. Taken together, our results show that the simultaneous inhibition of critical prosurvival kinases by KP372-1 leads to mitochondrial dysfunction and apoptosis of AML but not normal hematopoietic progenitor cells.
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PMID:Simultaneous inhibition of PDK1/AKT and Fms-like tyrosine kinase 3 signaling by a small-molecule KP372-1 induces mitochondrial dysfunction and apoptosis in acute myelogenous leukemia. 1658


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