UMLS:C0023473 - FACTA Search

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Query: UMLS:C0023473 (chronic myeloid leukemia)
18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CRKL is a 39 kDa adapter protein, originally cloned in proximity to the BCR gene on chromosome 22, which has a key regulatory role in hematopoietic cells. CRKL has one SH2 and two SH3 domains, with 60% homology to CRK II. CRKL is a prominent substrate of the BCR/ABL oncoprotein in chronic myelogenous leukemia and binds to both BCR/ABL and c-ABL. CRKL has been shown to be tryosine phosphorylated in response to normal hematopoietic growth factor receptor signaling with ligands such as thrombopoietin, erythropoietin or steel factor. Additionally, CRKL is involved in signaling initiated by crosslinking of beta integrins, and B cell or T cell receptors. Structurally, the amino-terminal SH3 domain of CRKL has been shown to bind proteins such as C3G, SOS, PI3-K, c-ABL or BCR/ABL. The SH2 domain of CRKL can bind to tyrosine phosphorylated proteins such as CBL, HEF1, CAS or paxillin. This review summarizes the current knowledge on the function of this unique adapter protein in normal hematopoietic and leukemic cell signaling.
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PMID:Role of the adapter protein CRKL in signal transduction of normal hematopoietic and BCR/ABL-transformed cells. 959 59

Bcr-Abl is an oncogenic tyrosine kinase expressed in tumor cells of CML and a subset of ALL which in its unregulated and activated state is thought to cause cell transformation and leukemia. Bcr-Abl contains several autophosphorylation sites which serve as potential docking sites for SH2-containing signaling molecules. Mutational analysis has indicated that these autophosphorylation sites play a critical role in the transforming capability of Bcr-Abl. It has been shown that the SH2-containing adapter protein Grb2 binds to the autophosphorylation site Tyr(p)177 whereby it couples Bcr-Abl to the Ras pathway. The biological consequences of this interaction, however, are presently unclear. A Tyr177-mutated Bcr-Abl which lacks the ability to interact with the Grb2-SH2 domain still transforms myeloid cells and generates tumors in nude mice. We performed a yeast two-hybrid screen to identify signaling proteins which bind to distinct Bcr-Abl autophosphorylation sites. Autophosphorylation of Bcr-Abl in yeast was accomplished by using the DNA binding protein LexA which permits dimerization and crossphosphorylation of the fused bait. Using a LexA-Bcr-Abl full length fusion protein as bait, we identified several SH2-containing proteins. Among them we confirmed molecules already shown by others to interact with Bcr-Abl, in vivo, including Grb2, PI-3-kinase and Crk indicating that dimerization in yeast leads to autophosphorylation of tyrosine residues crucial for Bcr-Abl signaling in vivo. More importantly, we identified the SH2-containing protein Grb10 as a new binding partner for Bcr-Abl. This binding occurs in a phosphotyrosine-dependent manner at Bcr sites of Bcr-Abl. Both Abl and Bcr alone, as well as a kinase-defective Bcr-Abl, failed to interact with Grb10 in yeast. Mutational analysis uncovered a new SH2 binding site in Bcr-Abl located between Bcr aa242-446, which is different from the Grb2 binding site. Binding could be demonstrated in vitro and also in vivo as shown by co-immunoprecipitation analysis in CML cells. Using a temperature sensitive Bcr-Abl stably overexpressed in hematopoetic cells, we demonstrated that complex formation of Grb10 with Bcr-Abl was kinase activation-dependent in vivo. Notably, a Bcr-Abl mutant protein (Bcr/1-242-Abl) which lacks the ability to interact with Grb10 partially alleviated IL-3 dependence of Ba/F3 cells, indicating that the Grb10/Bcr-Abl interaction is important for Bcr-Abl-induced IL-3 independence of Ba/F3 cells. In addition, the Bcr/1-242-Abl mutant has a reduced capacity to induce focus formation in fibroblasts.
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PMID:The SH2-containing adapter protein GRB10 interacts with BCR-ABL. 974 73

To study the oncogenic role of the p210(bcr-abl) fusion protein in chronic myelogenous leukemia cells, we generated a mouse cell line that was stably transfected with and overexpressed the human p210(bcr-abl) fusion protein. We then looked for phosphorylation activation of the Janus-activated kinase (JAK) family of tyrosine-specific protein kinases by the p210(bcr-abl) fusion protein. We found that JAK1, which has been shown by others to be associated with the IFN-alpha and -gamma plasma membrane receptors, was phosphorylated to a much greater degree in cells containing the p210(bcr-abl) fusion protein than was the case in the original, untransfected cell line. In contrast, no phosphorylation of the JAK2 kinase, which is associated with the IFN-gamma but not IFN-alpha receptor, was observed either with or without p210(bcr-abl) protein. A substrate of JAK1, STAT1 (signal transducers and activators of transcription 1), was found to be phosphorylated in cells containing overexpressed p210(bcr-abl) fusion protein. These results indicate that the presence of the p210(bcr-abl) protein kinase within a cell is associated with phosphorylation of the JAK1 kinase and its substrate STAT1.
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PMID:Potential role of bcr-abl in the activation of JAK1 kinase. 981 65

Abnormal beta1 integrin receptor function may contribute to the continuous proliferation and abnormal circulation of malignant hematopoietic progenitors in chronic myelogenous leukemia (CML). Previous studies suggest that abnormal integrin function in CML progenitors is related to the presence of the BCR/ABL oncogene. BCR/ABL may alter integrin function in CML by phosphorylating cytoskeletal and/or signaling proteins important for normal integrin function. We evaluated the effect of Tyrphostin AG957, a protein tyrosine kinase (PTK) inhibitor which has activity against the p210BCR/ABL kinase, on beta1 integrin function in CML progenitors. Incubation of CML marrow CD34+HLA-DR+ cells with Tyrphostin AG957 at concentrations that did not affect colony-forming cells (CFC) viability, but which partly inhibited p210BCR/ABL kinase activity, significantly increased CML CFC adhesion to stroma and alpha4beta1 and alpha5beta1 integrin binding fragments of fibronectin (FN). CML CFC proliferation, unlike that of normal CFC, is not inhibited following integrin receptor engagement with FN or anti-integrin antibodies. AG957 did not alter CML CFC proliferation by itself, but resulted in significant inhibition of CML CFC proliferation following integrin engagement. Another PTK inhibitor, Tyrphostin AG555, which does not have anti-p210BCR/ABL kinase activity, did not affect CML CFC adhesion or proliferation. Neither AG957 nor AG555 affected normal CFC adhesion or proliferation. In BCR/ABL expressing cells, AG957 partially inhibited phosphorylation of several proteins that are BCR/ABL PTK substrates and are involved in normal integrin signaling. These studies suggest that abnormal tyrosine phosphorylation may play an important role in defective integrin function in CML progenitors.
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PMID:Tyrphostin AG957, a tyrosine kinase inhibitor with anti-BCR/ABL tyrosine kinase activity restores beta1 integrin-mediated adhesion and inhibitory signaling in chronic myelogenous leukemia hematopoietic progenitors. 982 45

Several studies indicate that a number of signal-transducing molecules involved in the proliferation, differentiation, and functional activation of normal hemopoietic cells may be constitutively activated in primary leukemic cells and play a role in the outcome or in the progression of these neoplastic disorders. In this study we show that the product of the proto-oncogene c-Cbl, whose function is still unknown, is constitutively tyrosine phosphorylated not only in cells from chronic myelogenous leukemias (CMLs) in the blast phase, but also in cells from acute myeloblastic leukemias (AMLs), Ph-negative acute T-lymphoblastic leukemias (T-ALLs), and Ph-negative pre-B lymphoblastic leukemias (pre-B ALL). Moreover, in acute leukemia cells, c-Cbl was not stably complexed with the tyrosine-phosphorylated adaptor protein CrkL. The analysis of Grb2/c-Cbl interaction demonstrated that, in both acute leukemia and CML blasts, c-Cbl was stably complexed with the N-terminal Src homology (SH) 3 domain of Grb2 and, in blasts from ALL patients, with the Grb2 SH2 domain. The analysis of c-Cbl subcellular distribution showed that in all cases of leukemia tested, as well as in growth factor-stimulated M-07e cells, c-Cbl was present in the cytosolic, in the membrane, and in the detergent-insoluble fractions. Finally, in polymorphonuclear neutrophils (PMNs) from CML patients, c-Cbl was found stably associated with the detergent-insoluble fraction, whereas in PMNs from normal donors, it was detected only in the cytosolic fraction. Our findings that c-Cbl is constitutively tyrosine phosphorylated and associated with the detergent-insoluble fraction in AML and ALL blasts and in PMNs from CML patients suggest that this event represents a common step in the neoplastic transformation of both myeloid and lymphoid progenitor cells.
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PMID:c-Cbl tyrosine phosphorylation and subcellular localization in human primary leukemic cells. 984 79

Crkl, a 39-kD SH2, SH3 domain-containing adapter protein, is constitutively tyrosine phosphorylated in hematopoietic cells from chronic myelogenous leukemia (CML) patients. We recently reported that thrombopoietin induces tyrosine phosphorylation of Crkl in normal platelets. In this study, we demonstrate that thrombopoietin induces association of Crkl with a tyrosine phosphorylated 95- to 100-kD protein in platelets and in UT7/TPO cells, a thrombopoietin-dependent megakaryocytic cell line. With specific antibodies against STAT5, we demonstrate that the 95- to 100-kD protein in Crkl immunoprecipitates is STAT5. This coimmunoprecipitation was specific in that Crkl immunoprecipitates do not contain STAT3, although STAT3 becomes tyrosine phosphorylated in thrombopoietin-stimulated platelets. The coimmunoprecipitaion of Crkl with STAT5 was inhibited by the immunizing peptide for Crkl antisera or phenyl phosphate (20 mmol/L). After denaturing of Crkl immunoprecipitates, Crkl was still immunoprecipitated by Crkl antisera. However, coimmunoprecipitation of STAT5 was not observed. Coincident with STAT5 tyrosine phosphorylation, thrombopoietin induces activation of STAT5 DNA-binding activity as demonstrated by electrophoretic mobility shift assays (EMSA). Using a beta-casein promoter STAT5 binding site as a probe, we have also demonstrated that Crkl antisera supershift the STAT5-DNA complex, suggesting that Crkl is a component of the complex in the nucleus. Furthermore, interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and erythropoietin also induce Crkl-STAT5 complex formation in responding cells in a stimulation-dependent manner. In vitro, glutathione S-transferase (GST)-Crkl bound to STAT5 inducibly through its SH2 domain. These results indicate that thrombopoietin, IL-3, GM-CSF, and erythropoietin commonly induce association of STAT5 and Crkl and that the complex translocates to the nucleus and binds to DNA. Interestingly, such association between STAT5 and Crkl was not observed in cytokine-stimulated murine cells, suggesting an intriguing possibility that components of the human STAT5-DNA complex may be different from those of the murine counterpart.
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PMID:Thrombopoietin induces association of Crkl with STAT5 but not STAT3 in human platelets. 984 31

We investigated tyrosine phosphorylation of proteins in primary human leukemia cells stimulated by granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), interleukin-3 (IL-3), tumor necrosis factor (TNF), thrombopoietin (TPO) and phorbol myristate acetate (PMA) in 61 patients with acute myeloid leukemia (AML), nine patients with chronic myeloid leukemia (CML) in blastic crisis and four patients in chronic phase, and compared these data of leukemia with those of normal human immature hematopoietic cells. These cytokines and PMA induced tyrosine phosphorylation of proteins in a manner characteristic for each cytokine or PMA in AML cells. G-CSF, GM-CSF and IL-3 frequently phosphorylated p92, p80, p70, p44 and p42. p95 was frequently phosphorylated by G-CSF, and was phosphorylated in one third of the cases by TPO. On the other hand, TNF selectively induced tyrosine phosphorylation of p42, and PMA selectively induced that of p44 and p42. In marked contrast to AML cells, CML cells responded poorly to cytokines with protein tyrosine phosphorylation, and normal human bone marrow mononuclear cells and CD34-positive cells also showed poor response to cytokines. The results of the immunoprecipitation studies showed tyrosine phosphorylation of signal transducers and activators of transcription (Stat) 5 induced by G-CSF, GM-CSF, IL-3 and/or TPO in six cases, that of extracellular signal-regulated kinase (ERK) by GM-CSF in two cases and that of p38 by TNF in three cases. Intracellular amount of Stat5 was markedly increased in AML cells compared with that in CML cells and normal human bone marrow cells. whereas intracellular amount of ERK and p38 was uniformly abundant in both leukemic and normal cells. These results show cytokine-specific and amplified tyrosine phosphorylation of proteins in AML cells and suggest that amplified response might, at least in part, result from the increased amount of signaling molecules such as Stat5.
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PMID:Tyrosine phosphorylation of proteins in primary human myeloid leukemia cells stimulated by cytokines: analysis of the frequency of phosphorylation, and partial identification and semi-quantification of signaling molecules. 988 38

The SH2-SH3 domain-containing adaptor protein CRKL is the predominant tyrosine phosphorylated protein in chronic myelogenous leukemia (CML) neutrophils and BCR-ABL-expressing cell lines. The amino terminal CRKL SH3 domain binds directly to a proline-rich region in the C-terminus of BCR-ABL. BCR-ABL mutants with deletions of this region were constructed to assess biologic effects of eliminating the CRKL binding site. Yeast two-hybrid analysis and gel overlay assays show eradication of the direct interaction of CRKL with BCR-ABL in the proline deletion mutants. However, these BCR-ABL mutants transform myeloid cells to growth factor independence, and in these cells CRKL is tyrosine phosphorylated and associates with BCR-ABL. These findings suggest both direct and indirect interactions of CRKL with BCR-ABL. Thus, disruption of the direct interaction with BCR-ABL has not excluded a role for CRKL in BCR-ABL-mediated transformation.
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PMID:CRKL binding to BCR-ABL and BCR-ABL transformation. 1019 28

Because of the probable causal relationship between constitutive p210(bcr/abl) protein tyrosine kinase activity and manifestations of chronic-phase chronic myelogenous leukemia (CML; myeloid expansion), a key goal is to identify relevant p210 substrates in primary chronic-phase CML hematopoietic progenitor cells. We describe here the purification and mass spectrometric identification of a 155-kD tyrosine phosphorylated protein associated with src homologous and collagen gene (SHC) from p210(bcr/abl)-expressing hematopoietic cells as SHIP2, a recently reported, unique SH2-domain-containing protein closely related to phosphatidylinositol polyphosphate 5-phosphatase SHIP. In addition to an N-terminal SH2 domain and a central catalytic region, SHIP2 (like SHIP1) possesses both potential PTB(NPXY) and SH3 domain (PXXP) binding motifs. Thus, two unique 5-ptases with striking structural homology are coexpressed in hematopoietic progenitor cells. Stimulation of human hematopoietic growth factor responsive cell lines with stem cell factor (SCF), interleukin-3 (IL-3), and granulocyte-macrophage colony-stimulating factor (GM-CSF) demonstrate the rapid tyrosine phosphorylation of SHIP2 and its resulting association with SHC. This finding suggests that SHIP2, like that reported for SHIP1 previously, is linked to downstream signaling events after activation of hematopoietic growth factor receptors. However, using antibodies specific to these two proteins, we demonstrate that, whereas SHIP1 and SHIP2 selectively hydrolyze PtdIns(3,4,5)P3 in vitro, only SHIP1 hydrolyzes soluble Ins(1,3,4,5)P4. Such an enzymatic difference raises the possibility that SHIP1 and SHIP2 may serve different functions. Preliminary binding studies using lysates from p210(bcr/abl)-expressing cells indicate that both Ptyr SHIP2 and Ptyr SHIP1 bind to the PTB domain of SHC but not to its SH2 domain. Interestingly, SHIP2 was found to selectively bind to the SH3 domain of ABL, whereas SHIP1 selectively binds to the SH3 domain of Src. Furthermore, in contrast to SHIP1, SHIP2 did not bind to either the N-terminal or C-terminal SH3 domains of GRB2. These observations suggest (1) that SHIP1 and SHIP2 may have a different hierarchy of binding SH3 containing proteins and therefore may modulate different signaling pathways and/or localize to different cellular compartments and (2) that they may be substrates for tyrosine phosphorylation by different tyrosine kinases. Because recent evidence has clearly implicated both PI(3,4, 5)P3 and PI(3,4)P2 in growth factor-mediated signaling, our finding that both SHIP1 and SHIP2 are constitutively tyrosine phosphorylated in CML primary hematopoietic progenitor cells may thus have important implications in p210(bcr/abl)-mediated myeloid expansion.
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PMID:A novel SH2-containing phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP2) is constitutively tyrosine phosphorylated and associated with src homologous and collagen gene (SHC) in chronic myelogenous leukemia progenitor cells. 1019 51

The chimeric oncogene bcr-abl is detected in virtually every case of chronic myelogenous leukemia. It has been shown that cells (such as K562) expressing Bcr-Abl/p210, a protein tyrosine kinase, not only undergo cellular transformation but also demonstrate multiple drug resistance. Recent studies also demonstrate that the proteasome is involved in the survival signaling pathway(s). In the current study, we tested the hypothesis that the proteasome might play a role in regulating Bcr-Abl function. We have demonstrated by using a variety of inhibitors that inhibition of the proteasome, but not of the cysteine protease, activity is able to activate the apoptotic cell death program in K562 cells. Proteasome inhibition-induced apoptosis is demonstrated by condensation and fragmentation of nuclei, appearance of an apoptotic population with sub-G1 DNA content, the internucleosomal fragmentation of DNA, and cleavage of poly(ADP-ribose) polymerase, and can be blocked by a specific caspase-3-like tetrapeptide inhibitor. Western blot analysis with specific antibodies to c-Abl and Bcr proteins show that treatment of K562 cells with a proteasome inhibitor results in significant reduction of Bcr-Abl protein expression, which occurs several hours before the onset of apoptotic execution. Levels of c-Abl/p145 and Bcr/p160 proteins, however, remain essentially unaltered at that time. Furthermore, reduced Bcr-Abl expression is reflected in significantly attenuated Bcr-Abl-mediated protein tyrosine phosphorylation. Taken together, these results indicate that proteasome inhibition is sufficient to inactivate Bcr-Abl function and subsequently activate the apoptotic death program in cells that are resistant to apoptosis induced by chemotherapy.
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PMID:Proteasome inhibition leads to significant reduction of Bcr-Abl expression and subsequent induction of apoptosis in K562 human chronic myelogenous leukemia cells. 1021 53

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