Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Erythropoietin (Epo)-independent differentiation of erythroid progenitors is a major characteristic of myeloproliferative disorders, including chronic myeloid leukemia. Epo receptor (EpoR) signaling is crucial for normal erythroid development, as evidenced by the properties of Epo(-/-) and EpoR(-/-) mice, which contain a normal number of fetal liver erythroid progenitors but die in utero from a severe anemia attributable to the absence of red cell maturation. Here we show that two constitutively active cytoplasmic protein tyrosine kinases, P210(BCR-ABL) and v-SRC, can functionally replace the EpoR and support full proliferation, differentiation, and maturation of fetal liver erythroid progenitors from EpoR(-/-) mice. These protein tyrosine kinases can also partially complement the myeloid growth factors IL-3, IL-6, and Steel factor, which are normally required in addition to Epo for erythroid development. Additionally, BCR-ABL mutants that lack residues necessary for transformation of fibroblasts or bone marrow cells can fully support normal erythroid development. These results demonstrate that activated tyrosine kinase oncoproteins implicated in tumorigenesis and human leukemia can functionally complement for cytokine receptor signaling pathways to support normal erythropoiesis in EpoR-deficient cells. Moreover, terminal differentiation of erythroid cells requires generic signals provided by activated protein tyrosine kinases and does not require a specific signal unique to a cytokine receptor.
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PMID:BCR-ABL and v-SRC tyrosine kinase oncoproteins support normal erythroid development in erythropoietin receptor-deficient progenitor cells. 1055 95

The c-Fes protein-tyrosine kinase exhibits strong expression in myeloid hematopoietic cells. Previous studies have shown that Fes induces differentiation in the chronic myelogenous leukemia-derived cell line K-562, suggesting that the Fes signal for differentiation is dominant to the Bcr-Abl signal for transformation in these cells. In addition, Fes has been shown to associate with and phosphorylate Bcr on NH2-terminal sequences retained within Bcr-Abl. To determine whether Fes interacts directly with Bcr-Abl, kinase-inactive Bcr-Abl was coexpressed with Fes in 293T cells, and phosphorylation was assessed by anti-phosphotyrosine immunoblotting. Bcr-Abl was strongly phosphorylated by Fes under these conditions, suggestive of direct interaction. Similarly, tyrosine phosphorylation of kinase-inactive Fes was observed after coexpression with active Bcr-Abl. To test for the interaction of Fes with Bcr-Abl under physiological conditions, wild-type and kinase-defective Fes were stably expressed in the cytokine-dependent myeloid leukemia cell line, DAGM. Expression of either form of Fes alone did not affect the proliferation or interleukin 3 dependence of these cells. The DAGM/Fes cells were then infected with Bcr-Abl retroviruses, and their rates of cytokine-independent outgrowth were compared. Fes dramatically suppressed Bcr-Abl-induced DAGM cell outgrowth relative to a cell line expressing beta-galactosidase as a negative control. This effect required Fes tyrosine kinase activity, because the kinase-inactive form of Fes did not affect Bcr-Abl-induced cell outgrowth. The phosphotyrosine content of both wild-type and kinase-inactive Fes was strongly enhanced after coexpression with Bcr-Abl in DAGM cells, similar to the 293T result. Phosphorylation of wild-type Fes correlated with stimulation of Fes tyrosine kinase activity in the presence of Bcr-Abl. These results show that Fes and Bcr-Abl interact in myeloid cells, leading to Fes activation and suppression of Bcr-Abl-induced conversion to cytokine independence.
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PMID:The c-Fes protein-tyrosine kinase suppresses cytokine-independent outgrowth of myeloid leukemia cells induced by Bcr-Abl. 1070 30

Bcr-Abl-expressing leukemic cells are highly resistant to apoptosis induced by chemotherapeutic drugs. Although a number of signaling molecules have been shown to be activated by the Bcr-Abl kinase, the antiapoptotic pathway triggered by this oncogene has not been elucidated. Here, we show that the interleukin 3-independent expression of the antiapoptotic protein, Bcl-xL, is induced by Bcr-Abl through activation of signal transducer and activator of transcription (Stat)5. Inhibition of the Bcr-Abl kinase activity in Bcr-Abl-expressing cell lines and CD34(+) cells from chronic myelogenous leukemia (CML) patients induces apoptosis by suppressing the capacity of Stat5 to interact with the bcl-x promoter. Interestingly, after inhibition of the Bcr-Abl kinase, the expression of Bcl-xL is downregulated more rapidly in chronic phase than in blast crisis CML cells, suggesting an involvement of this protein in disease progression. Overall, we describe a novel antiapoptotic pathway triggered by Bcr-Abl that may contribute to the resistance of CML cells to undergo apoptosis.
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PMID:Blockade of the Bcr-Abl kinase activity induces apoptosis of chronic myelogenous leukemia cells by suppressing signal transducer and activator of transcription 5-dependent expression of Bcl-xL. 1072 59

Neoplastic CD34+ cells from chronic myeloid leukemia (CML) patients proliferate in vitro in the absence of serum or defined growth factors due to an autocrine mechanism involving IL-3 and G-CSF (Jiang et al. Proc Natl Acad Sci USA 1999; 96: 12804). Detailed examination of the various cell types produced in such cultures has now demonstrated the rapid, factor-independent, generation of clonogenic progenitors for all lineages (granulocyte-macrophage, megakaryocyte and erythroid) with the additional appearance within 10 days of large numbers of mature granulocytes, macrophages, and megakaryocytes, as well as occasional erythroid cells. Inclusion of flt3-ligand, Steel factor, IL-3, IL-6, and G-CSF +/- erythropoietin (EPO) in the cultures enhanced only slightly the output of mature cells (except for the erythroid population which was much larger when EPO was added). Analogous subpopulations of normal CD34+ cells produced similar numbers and types of cells but, as expected, only when growth factors were added. Thus primitive CD34+ CML cells proliferating autonomously in vitro recapitulate the full spectrum of differentiation responses of normal CD34+ cells stimulated by IL-3 and G-CSF. These findings point to a role of autocrine IL-3 and G-CSF in the similar multi-lineage expansion of differentiating CD34+ CML cells that occurs in vivo.
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PMID:Autonomous multi-lineage differentiation in vitro of primitive CD34+ cells from patients with chronic myeloid leukemia. 1086 77

Ex vivo culture of CD34+ has the potential to provide large numbers of cells for clinical use in autologous and allogeneic transplantation and for experimental research involving genetic manipulation. We evaluated the ex vivo expansion of CD34+ cells obtained from bone marrow (BM) and peripheral blood (PB) of untreated patients with chronic myeloid leukaemia (CML) in the chronic phase and compared these results with those obtained from BM from normal volunteers (NBM) and peripheral blood after mobilising chemotherapy from patients with non-haematological disorders (MPB). Selected CD34+ cells were stimulated with interleukin 1(beta), interleukin IL-3, interleukin IL-6 and stem cell factor. The proliferation observed in patients with CML was similar to that seen in normal donors. CD34+ cells derived from patients with CML are more differentiated than their normal counterparts, as shown by the coexpression of CD34 and CD33 antigens on day 0 (85.6% for CML-BM and 76.8% for CML-PB). The culture conditions allowed a significant expansion of granulocyte-macrophage colony-forming units (CFU-GM) from NBM (33-fold increase) and MPB (22-fold increase), in contrast with CML-derived BM and PB CD34+ cells (2.3-fold increase). These results indicate that the optimal time to harvest ex vivo expanded cells is dependent on a critical compromise between cell numbers and successful retention of their repopulating potential.
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PMID:Ex vivo expansion and characterisation of CD34+ cells derived from chronic myeloid leukaemia bone marrow and peripheral blood, and from normal bone marrow and mobilised peripheral blood. 1099 28

Aberrant expression of FLT3 has been found in most cases of B-lineage ALL and AML, and subsets of T cell ALL, CML in blast crisis and CLL. In 20% of patients with AML the receptor has small internal tandem duplications of the juxtamembrane region which appear to contitutively activate the receptor. To investigate whether FLT3 activation could play a role in leukemia, we generated a constitutively activated FLT3 by fusing its cytoplasmic domain to the helix-loop-helix domain of TEL in analogy to the fusion that occurs with TEL-PDGFR in CMML. In vitro translation assays demonstrated oligomerization and intrinsic tyrosine kinase activity of the TEL-FLT3 chimeric receptor. Constitutively activated TEL-FLT3 conferred IL-3 independence and long-term proliferation to transfected Ba/F3 cells. Immunoblot analyses showed that JAK 2, STAT 3, STAT 5a, STAT 5b and CBL were tyrosine-phosphorylated in TEL-FLT3 expressing Ba/F3 cells in the absence of IL-3. These data suggest a possible role for the JAK/STAT pathway in FLT3 signaling. Transplantation of TEL-FLT3 expressing Ba/F3 cells into syngeneic mice caused mortality in all mice by 3 weeks after injection. Histopathologic analysis demonstrated a massive infiltration of mononuclear cells in the liver, spleen and bone marrow. The mimicking of naturally occurring TEL fusions provides an approach to assess aspects of the biology of activated FLT3, or other receptor-type tyrosine kinases (RTKs) in leukemic transformation.
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PMID:Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation. 1102 52

Primitive hematopoietic progenitors from some patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) express aberrant transcripts for interleukin 3 (IL-3) and granulocyte colony-stimulating factor (G-CSF), and exhibit autonomous proliferation in serum-free cultures that is inhibited by anti-IL-3 and anti-IL-3 receptor antibodies. Expression of the product of the Ph chromosome, the BCR/ABL oncogene, in mice by retroviral bone marrow transduction and transplantation induces CML-like leukemia, and some leukemic mice have increased circulating IL-3, and perhaps granulocyte-macrophage colony-stimulating factor (GM-CSF). These observations raise the possibility of autocrine or paracrine cytokine production in the pathogenesis of human CML. Mice with homozygous inactivation of the Il-3 gene, the Gm-csf gene, or both, were used to test the requirement for these cytokines for induction of CML-like disease by BCR/ABL. Neither IL-3 nor GM-CSF was required in donor, recipient, or both for induction of CML-like leukemia by p210 BCR/ABL. Use of novel mice deficient in both IL-3 and GM-CSF demonstrated that the lack of effect on leukemogenesis was not due to redundancy between these hematopoietic growth factors. Analysis of cytokine levels in leukemic mice where either donor or recipient was Il-3(-/-) indicated that the increased IL-3 originated from the recipient, suggestive of a host reaction to the disease. These results demonstrate that IL-3 and GM-CSF are not required for BCR/ABL-induced CML-like leukemia in mice and suggest that autocrine production of IL-3 does not play a role in established chronic phase CML in humans.
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PMID:Interleukin 3 and granulocyte-macrophage colony-stimulating factor are not required for induction of chronic myeloid leukemia-like myeloproliferative disease in mice by BCR/ABL. 1122 92

Bcr/abl fusion gene, in experimental models, induces survival to growth factor deprivation and hypersensitivity to IL3. However, conflicting data were reported about chronic myeloid leukemia (CML) progenitors. We investigated the responsiveness of purified CML CFU-GM to GM-CSF/IL3 and their survival to growth factor deprivation. CFU-GM hypersensitivity to IL3 and/or GM-CSF was found in 3/11 CML cases only. CML CFU-GM survived well in stroma-free 'mass' culture (5 x 10(4) cells/ml) without cytokine addition, up to day 11, average recovery being around 95% in medium + 10% fetal bovine serum and 67-81% in serum-free medium. Conversely, normal progenitors declined steadily, particularly after extensive purification (18 +/- 10% recovery at the 7th day), and in serum-free medium (4 +/- 6% recovery). By contrast, normal and CML CFU-GM declined in a similar way in limiting dilution cultures (1-10 cells/50 microl). We also investigated the effects of retinoic acid and alpha-interferon on CFU-GM survival. Both all-trans- and 13-cis retinoic acid, particularly in combination with alpha-interferon, reduced CML CFU-GM recovery down to normal progenitors' values. In conclusion, hypersensitivity to CSFs is rare in CML, whereas resistance to growth factor deprivation has been confirmed in mass, but not in limiting, dilution cultures. Both stereoisomers of retinoic acid, at therapeutic concentrations and in combination with alpha-interferon, can overcome the survival advantage of CML progenitors.
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PMID:Growth advantage of chronic myeloid leukemia CFU-GM in vitro: survival to growth factor deprivation, possibly related to autocrine stimulation, is a more common feature than hypersensitivity to GM-CSF/IL3 and is efficiently counteracted by retinoids +- alpha-interferon. 1123 66

The tyrosine kinase inhibitor STI571 inhibits BCR/ABL and induces hematologic remission in most patients with chronic myeloid leukemia. In addition to BCR/ABL, STI571 also inhibits v-Abl, TEL/ABL, the native platelet-derived growth factor (PDGF)beta receptor, and c-KIT, but it does not inhibit SRC family kinases, c-FMS, FLT3, the epidermal growth factor receptor, or multiple other tyrosine kinases. ARG is a widely expressed tyrosine kinase that shares substantial sequence identity with c-ABL in the kinase domain and cooperates with ABL to regulate neurulation in the developing mouse embryo. As described here, ARG has recently been implicated in the pathogenesis of leukemia as a fusion partner of TEL. A TEL/ARG fusion was constructed to determine whether ARG can be inhibited by STI571. When expressed in the factor-dependent murine hematopoietic cell line Ba/F3, the TEL/ARG protein was heavily phosphorylated on tyrosine, increased tyrosine phosphorylation of multiple cellular proteins, and induced factor-independent proliferation. The effects of STI571 on Ba/F3 cells transformed with BCR/ABL, TEL/ABL, TEL/PDGFbetaR, or TEL/ARG were then compared. STI571 inhibited tyrosine phosphorylation and cell growth of Ba/F3 cells expressing BCR/ABL, TEL/ABL, TEL/PDGFbetaR, and TEL/ARG with an IC(50) of approximately 0.5 microM in each case, but it had no effect on untransformed Ba/F3 cells growing in IL-3 or on Ba/F3 cells transformed by TEL/JAK2. Culture of TEL/ARG-transfected Ba/F3 cells with IL-3 completely prevented STI571-induced apoptosis in these cells, similar to what has been observed with BCR/ABL- or TEL/ABL-transformed cells. These results indicate that ARG is a target of the small molecule, tyrosine kinase inhibitor STI571.
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PMID:ARG tyrosine kinase activity is inhibited by STI571. 1129 Jun 9

During differentiation in vitro, Embryonic Stem (ES) cells generate both primitive erythroid and definitive myeloid lineages in a process that mimics hematopoiesis in the mammalian yolk sac. To investigate leukemic transformation of these embryonic hematopoietic progenitors, we infected differentiating cultures of ES cells with the Chronic Myeloid Leukemia-specific BCR/ABL oncoprotein. Following a period of liquid culture, we isolated two transformed subclones, EB57 and EB67, that retained characteristics of embryonic hematopoietic progenitors and induced a fatal leukemia in mice characterized by massive splenomegaly and granulocytosis. Histopathology of the spleen revealed an abundance of undifferentiated blast-like cells. Investigation of the clonal origins of the granulocytes in the peripheral blood demonstrated that the injected donor cells contributed modestly to the granulocyte population while the majority were host-derived. EB57 secretes IL-3 and unidentified cytokines that can stimulate autocrine and paracrine cell proliferation, presumably accounting for the reactive granulocytosis in diseased mice. These BCR/ABL transformed hematopoietic derivatives of ES cells recapitulate the relationship of BCR/ABL expression to IL-3 production that has been described for primitive hematopoietic progenitors from human CML patients, and illustrates the potential for autocrine and paracrine effects of BCR/ABL-infected cells in murine models.
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PMID:Autocrine and paracrine effects of an ES-cell derived, BCR/ABL-transformed hematopoietic cell line that induces leukemia in mice. 1142 Jun 75


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