Journal articles on the topic 'Abelson related gene'
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1
Ramakrishnan, L., Q. Wu, A. Yue, M. D. Cooper, and N. Rosenberg. "BP-1/6C3 expression defines a differentiation stage of transformed pre-B cells and is not related to malignant potential." Journal of Immunology 145, no. 5 (September 1, 1990): 1603–8. http://dx.doi.org/10.4049/jimmunol.145.5.1603.
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Abstract BP-1 antibody recognizes a cell surface molecule related to the zinc-dependent metallopeptidases that is expressed during a narrow window early in B cell differentiation. Expression of the same molecule, as originally recognized by the mAb 6C3, is widely accepted to be associated with the complete malignant transformation of pre-B lymphoid cells. We have examined BP-1/6C3 expression in a panel of established Abelson virus-transformed cells that includes both cells analogous to pre-B cells and to less differentiated B lineage cells that have not yet completed Ig H chain gene rearrangement. This analysis reveals that many of the less differentiated transformants do not express BP-1/6C3 for an extended culture period. In contrast, virtually all transformants that are analogous to normal pre-B cells express the determinant early in their culture history. The BP-1/6C3 negative transformants are fully tumorigenic in syngeneic mice, demonstrating that BP-1/6C3 expression is not required for complete malignant transformation. Our data thus suggest that the pattern of BP-1/6C3 expression in Abelson virus-transformed cells mimics that observed in normal cells and is indicative of a differentiation event unrelated to the malignant potential of the cells.
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Cazzaniga, Giovanni, Sabrina Tosi, Alessandra Aloisi, Giovanni Giudici, Maria Daniotti, Pietro Pioltelli, Lyndal Kearney, and Andrea Biondi. "The Tyrosine Kinase Abl-Related Gene ARG Is Fused toETV6 in an AML-M4Eo Patient With a t(1;12)(q25;p13): Molecular Cloning of Both Reciprocal Transcripts." Blood 94, no. 12 (December 15, 1999): 4370–73. http://dx.doi.org/10.1182/blood.v94.12.4370.
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Abstract The Ets variant gene 6 (ETV6/TEL) gene is rearranged in the majority of patients with 12p13 translocations fused to a number of different partners. We present here a case of acute myeloid leukemia M4 with eosinophilia (AML-M4Eo) positive for the CBFb/MYH11 rearrangement and carrying a t(1;12)(q25;p13) that involves the ETV6 gene at 12p13. By 3′rapid amplification of cDNA ends-polymerase chain reaction (3′RACE-PCR), a novel fusion transcript was identified between the ETV6 and the Abelson-related gene (ARG) at 1q25, resulting in a chimeric protein consisting of the HLH oligomerization domain of ETV6 and the SH2, SH3, and protein tyrosine kinase (PTK) domains of ARG. The reciprocal transcript ARG-ETV6 was also detected in the patient RNA by reverse transcriptase-polymerase chain reaction (RT-PCR), although at a lower expression level. The ARG gene encodes for a nonreceptor tyrosine kinase characterized by high homology with c-Abl in the TK, SH2, and SH3 domains. This is the first report on ARGinvolvement in a human malignancy.
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Cazzaniga, Giovanni, Sabrina Tosi, Alessandra Aloisi, Giovanni Giudici, Maria Daniotti, Pietro Pioltelli, Lyndal Kearney, and Andrea Biondi. "The Tyrosine Kinase Abl-Related Gene ARG Is Fused toETV6 in an AML-M4Eo Patient With a t(1;12)(q25;p13): Molecular Cloning of Both Reciprocal Transcripts." Blood 94, no. 12 (December 15, 1999): 4370–73. http://dx.doi.org/10.1182/blood.v94.12.4370.424k34_4370_4373.
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The Ets variant gene 6 (ETV6/TEL) gene is rearranged in the majority of patients with 12p13 translocations fused to a number of different partners. We present here a case of acute myeloid leukemia M4 with eosinophilia (AML-M4Eo) positive for the CBFb/MYH11 rearrangement and carrying a t(1;12)(q25;p13) that involves the ETV6 gene at 12p13. By 3′rapid amplification of cDNA ends-polymerase chain reaction (3′RACE-PCR), a novel fusion transcript was identified between the ETV6 and the Abelson-related gene (ARG) at 1q25, resulting in a chimeric protein consisting of the HLH oligomerization domain of ETV6 and the SH2, SH3, and protein tyrosine kinase (PTK) domains of ARG. The reciprocal transcript ARG-ETV6 was also detected in the patient RNA by reverse transcriptase-polymerase chain reaction (RT-PCR), although at a lower expression level. The ARG gene encodes for a nonreceptor tyrosine kinase characterized by high homology with c-Abl in the TK, SH2, and SH3 domains. This is the first report on ARGinvolvement in a human malignancy.
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Zeff, RA, YF Zhao, R. Tatake, H. Lachman, F. Borriello, and SG Nathenson. "Cis- and trans-repression of class I major histocompatibility gene expression in Abelson virus-transformed murine leukemia." Blood 78, no. 2 (July 15, 1991): 524–32. http://dx.doi.org/10.1182/blood.v78.2.524.524.
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Abstract Numerous tumor cell lines of leukemic origin are known to modulate cell surface expression of major histocompatibility complex (MHC) class I antigens resulting in alterations in their immune detection and tumorigenicity. We have been studying the mechanisms responsible for attenuation of MHC class I gene expression in an H-2 heterozygous (H-2b x H-2d) Abelson-Murine leukemia virus (A-MuLV)-transformed leukemic cell line (designated R8). Here we report that treatment of the R8 cell line with the protein synthesis inhibitor cycloheximide (CHX) increased H-2Kb steady-state messenger RNA (mRNA) levels several fold. The induced H-2Kb mRNA transcripts were functional, as demonstrated by their ability to be translated into immunoprecipitable H-2Kb alloantigen. H-2Kb null variants derived from the R8 cell line were shown to be the product of both cis- and trans-acting mechanisms, insomuch as the treatment of R8-derived H-2Kb non-expressor lines with CHX re-established expression of H-2Kb mRNA to the same extent as transfection of the variant cell line with the wild-type H-2Kb gene. Such findings indicate that downregulation of MHC class I gene expression is constitutive for the R8 leukemic cell line, a phenomenon that may be related to the immature pre-B-cell phenotype of this A-MuLV transformant.
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Zeff, RA, YF Zhao, R. Tatake, H. Lachman, F. Borriello, and SG Nathenson. "Cis- and trans-repression of class I major histocompatibility gene expression in Abelson virus-transformed murine leukemia." Blood 78, no. 2 (July 15, 1991): 524–32. http://dx.doi.org/10.1182/blood.v78.2.524.bloodjournal782524.
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Numerous tumor cell lines of leukemic origin are known to modulate cell surface expression of major histocompatibility complex (MHC) class I antigens resulting in alterations in their immune detection and tumorigenicity. We have been studying the mechanisms responsible for attenuation of MHC class I gene expression in an H-2 heterozygous (H-2b x H-2d) Abelson-Murine leukemia virus (A-MuLV)-transformed leukemic cell line (designated R8). Here we report that treatment of the R8 cell line with the protein synthesis inhibitor cycloheximide (CHX) increased H-2Kb steady-state messenger RNA (mRNA) levels several fold. The induced H-2Kb mRNA transcripts were functional, as demonstrated by their ability to be translated into immunoprecipitable H-2Kb alloantigen. H-2Kb null variants derived from the R8 cell line were shown to be the product of both cis- and trans-acting mechanisms, insomuch as the treatment of R8-derived H-2Kb non-expressor lines with CHX re-established expression of H-2Kb mRNA to the same extent as transfection of the variant cell line with the wild-type H-2Kb gene. Such findings indicate that downregulation of MHC class I gene expression is constitutive for the R8 leukemic cell line, a phenomenon that may be related to the immature pre-B-cell phenotype of this A-MuLV transformant.
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Pardanani, Animesh, and Ayalew Tefferi. "Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders." Blood 104, no. 7 (October 1, 2004): 1931–39. http://dx.doi.org/10.1182/blood-2004-01-0246.
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Abstract Imatinib mesylate is a small molecule drug that in vitro inhibits the Abelson (Abl), Arg (abl-related gene), stem cell factor receptor (Kit), and platelet-derived growth factor receptor A and B (PDGFRA and PDGFRB) tyrosine kinases. The drug has acquired therapeutic relevance because of similar inhibitory activity against certain activating mutations of these molecular targets. The archetypical disease in this regard is chronic myeloid leukemia, where abl is constitutively activated by fusion with the bcr gene (bcr/abl). Similarly, the drug has now been shown to display equally impressive therapeutic activity in eosinophilia-associated chronic myeloproliferative disorders that are characterized by activating mutations of either the PDGFRB or the PDGFRA gene. The former usually results from translocations involving chromosome 5q31-33, and the latter usually results from an interstitial deletion involving chromosome 4q12 (FIP1L1-PDGFRA). In contrast, imatinib is ineffective, in vitro and in vivo, against the mastocytosis-associated c-kit D816V mutation. However, wild-type and other c-kit mutations might be vulnerable to the drug, as has been the case in gastrointestinal stomal cell tumors. Imatinib is considered investigational for the treatment of hematologic malignancies without a defined molecular drug target, such as polycythemia vera, myelofibrosis with myeloid metaplasia, and acute myeloid leukemia.
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Ha, Byung Hak, Mark Adam Simpson, Anthony J. Koleske, and Titus J. Boggon. "Structure of the ABL2/ARG kinase in complex with dasatinib." Acta Crystallographica Section F Structural Biology Communications 71, no. 4 (March 20, 2015): 443–48. http://dx.doi.org/10.1107/s2053230x15004793.
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ABL2/ARG (ABL-related gene) belongs to the ABL (Abelson tyrosine-protein kinase) family of tyrosine kinases. ARG plays important roles in cell morphogenesis, motility, growth and survival, and many of these biological roles overlap with the cellular functions of the ABL kinase. Chronic myeloid leukemia (CML) is associated with constitutive ABL kinase activation resulting from fusion between parts of the breakpoint cluster region (BCR) andABL1genes. Similarly, fusion of theETV6(Tel) andARGgenes drives some forms of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Dasatinib is a tyrosine kinase inhibitor used for the treatment of CML by inhibiting ABL, and while it also inhibits ARG, there is currently no structure of ARG in complex with dasatinib. Here, the co-crystal structure of the mouse ARG catalytic domain with dasatinib at 2.5 Å resolution is reported. Dasatinib-bound ARG is found in the DFG-in conformation although it is nonphosphorylated on the activation-loop tyrosine. In this structure the glycine-rich P-loop is found in a relatively open conformation compared with other known ABL family–inhibitor complex structures.
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Lapetina, Stefanie, Christopher C. Mader, Kazuya Machida, Bruce J. Mayer, and Anthony J. Koleske. "Arg interacts with cortactin to promote adhesion-dependent cell edge protrusion." Journal of Cell Biology 185, no. 3 (May 4, 2009): 503–19. http://dx.doi.org/10.1083/jcb.200809085.
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The molecular mechanisms by which the Abelson (Abl) or Abl-related gene (Arg) kinases interface with the actin polymerization machinery to promote cell edge protrusions during cell–matrix adhesion are unclear. In this study, we show that interactions between Arg and the Arp2/3 complex regulator cortactin are essential to mediate actin-based cell edge protrusion during fibroblast adhesion to fibronectin. Arg-deficient and cortactin knockdown fibroblasts exhibit similar defects in adhesion-dependent cell edge protrusion, which can be restored via reexpression of Arg and cortactin. Arg interacts with cortactin via both binding and catalytic events. The cortactin Src homology (SH) 3 domain binds to a Pro-rich motif in the Arg C terminus. Arg mediates adhesion-dependent phosphorylation of cortactin, creating an additional binding site for the Arg SH2 domain. Mutation of residues that mediate Arg–cortactin interactions abrogate the abilities of both proteins to support protrusions, and the Nck adapter, which binds phosphocortactin, is also required. These results demonstrate that interactions between Arg, cortactin, and Nck1 are critical to promote adhesion-dependent cell edge protrusions.
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De Keersmaecker, Kim, Carlos Graux, Maria D. Odero, Nicole Mentens, Riet Somers, Johan Maertens, Iwona Wlodarska, et al. "Fusion of EML1 to ABL1 in T-cell acute lymphoblastic leukemia with cryptic t(9;14)(q34;q32)." Blood 105, no. 12 (June 15, 2005): 4849–52. http://dx.doi.org/10.1182/blood-2004-12-4897.
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Abstract The BCR-ABL1 fusion kinase is frequently associated with chronic myeloid leukemia and B-cell acute lymphoblastic leukemia but is rare in T-cell acute lymphoblastic leukemia (T-ALL). We recently identified NUP214-ABL1 as a variant ABL1 fusion gene in 6% of T-ALL patients. Here we describe the identification of another ABL1 fusion, EML1-ABL1, in a T-ALL patient with a cryptic t(9;14)(q34;q32) associated with deletion of CDKN2A (p16) and expression of TLX1 (HOX11). Echinoderm microtubule-associated protein-like 1-Abelson 1 (EML1-ABL1) is a constitutively phosphorylated tyrosine kinase that transforms Ba/F3 cells to growth factor-independent growth through activation of survival and proliferation pathways, including extracellular signal-related kinase 1/2 (Erk1/2), signal transducers and activators of transcription 5 (Stat5), and Lyn kinase. Deletion of the coiled-coil domain of EML1 abrogated the transforming properties of the fusion kinase. EML1-ABL1 and breakpoint cluster region (BCR)-ABL1 were equally sensitive to the tyrosine kinase inhibitor imatinib. These data further demonstrate the involvement of ABL1 fusions in the pathogenesis of T-ALL and identify EML1-ABL1 as a novel therapeutic target of imatinib. (Blood. 2005;105:4849-4852)
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Sexl, Veronika, Roland Piekorz, Richard Moriggl, Juerg Rohrer, Michael P. Brown, Kevin D. Bunting, Kristen Rothammer, Martine F. Roussel, and James N. Ihle. "Stat5a/b contribute to interleukin 7–induced B-cell precursor expansion, but abl- andbcr/abl-induced transformation are independent of Stat5." Blood 96, no. 6 (September 15, 2000): 2277–83. http://dx.doi.org/10.1182/blood.v96.6.2277.
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Abstract The cytokines interleukin 7 (IL-7) and interleukin 4 (IL-4) regulate lymphoid differentiation and function and activate the transcription factor Stat5. Using mice deficient for the 2 highly related transcription factors, Stat5a and Stat5b (Stat5a/b−/−), we investigated the role of Stat5 for B-cell differentiation, expansion, and function. Peripheral blood B cells of Stat5-deficient mice are significantly reduced, but no proliferation defects in response to various mitogenic stimuli are found. Also, IgM and IgG1 antibody production and immunoglobulin class switching are not affected. Pre- and pro-B cells of Stat5-deficient animals were found to have reduced responses to IL-7. Pro- and pre-B cells are the target cells of the abloncogene and numerous studies have suggested that Stat5a/b is essential for transformation by derivatives of the Abelson(abl) gene. To assess the role of Stat5a/b in transformation, we have evaluated the ability of variousabl derivatives to transform cells from Stat5a/b-deficient mice in vitro or in vivo. We demonstrate that the absence of Stat5a/b is not essential for the induction of lymphoid or myeloid tumors in vivo or on the ability to transform bone marrow cells in vitro.
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Sexl, Veronika, Roland Piekorz, Richard Moriggl, Juerg Rohrer, Michael P. Brown, Kevin D. Bunting, Kristen Rothammer, Martine F. Roussel, and James N. Ihle. "Stat5a/b contribute to interleukin 7–induced B-cell precursor expansion, but abl- andbcr/abl-induced transformation are independent of Stat5." Blood 96, no. 6 (September 15, 2000): 2277–83. http://dx.doi.org/10.1182/blood.v96.6.2277.h8002277_2277_2283.
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The cytokines interleukin 7 (IL-7) and interleukin 4 (IL-4) regulate lymphoid differentiation and function and activate the transcription factor Stat5. Using mice deficient for the 2 highly related transcription factors, Stat5a and Stat5b (Stat5a/b−/−), we investigated the role of Stat5 for B-cell differentiation, expansion, and function. Peripheral blood B cells of Stat5-deficient mice are significantly reduced, but no proliferation defects in response to various mitogenic stimuli are found. Also, IgM and IgG1 antibody production and immunoglobulin class switching are not affected. Pre- and pro-B cells of Stat5-deficient animals were found to have reduced responses to IL-7. Pro- and pre-B cells are the target cells of the abloncogene and numerous studies have suggested that Stat5a/b is essential for transformation by derivatives of the Abelson(abl) gene. To assess the role of Stat5a/b in transformation, we have evaluated the ability of variousabl derivatives to transform cells from Stat5a/b-deficient mice in vitro or in vivo. We demonstrate that the absence of Stat5a/b is not essential for the induction of lymphoid or myeloid tumors in vivo or on the ability to transform bone marrow cells in vitro.
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Bianchi, Cristina, Barbara Torsello, Valentina Angeloni, Silvia Bombelli, Monica Soldi, Lara Invernizzi, Paola Brambilla, and Roberto A. Perego. "Eight full-length abelson related gene (Arg) isoforms are constitutively expressed in caki-1 cell line and cell distribution of two isoforms has been analyzed after transfection." Journal of Cellular Biochemistry 105, no. 5 (December 1, 2008): 1219–27. http://dx.doi.org/10.1002/jcb.21922.
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Chorzalska, Anna Dorota, John Morgan, Max Petersen, Diana O. Treaba, Adam J. Olszewski, John L. Reagan, and Patrycja Dubielecka. "Loss of Abelson Interactor-1 Is Linked to Inflammatory Hematopoiesis and Accelerated Aging of Hematopoietic System." Blood 132, Supplement 1 (November 29, 2018): 1285. http://dx.doi.org/10.1182/blood-2018-99-118393.
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Abstract Background: Hematopoietic stem cells (HSC) ensure homeostasis and lifelong maintenance of hematopoietic system, but with age, they gradually lose quiescence, self-renewal potential, and system restoration capacity. HSC aging results in a differentiation shift towards myeloid lineage, anemia, thrombocytosis, decrease in T and B cells, imbalance in macrophage function, and increased osteoclast activity. Mechanisms involved in HSC aging include increased mTOR activity and ROS production, impaired autophagy, epigenetic reprograming, and cumulative DNA damage. Intriguingly, cellular and molecular similarities between aging and inflammation have led to a novel concept of "inflammation-associated aging of hematopoiesis". Understanding the molecular mechanisms responsible for this process may impact strategies targeting age-related diseases, including neoplasms. However, to date only few primary animal models of inflammation have shown bone marrow failure, so new animal models need to be established to provide mechanistic insight into the long-term implications of chronic inflammation on the hematopoietic system. We have previously shown that bone marrow-specific deletion of an adapter protein Abelson interactor-1 (Abi1) leads to a myeloproliferative neoplasm (MPN)-like disease in 35-56-week-old mice, mechanistically associated with increased activity of Src Family Kinases (SFKs), STAT3 and NF-κB. At both transcript and protein levels, Abi-1 is also significantly reduced in HSCs and granulocytes from patients with primary myelofibrosis (PMF), and Abi-1-deficient HSC in human PMF show increased SFK-STAT3-NF-κB signaling (Chorzalska, ASH 2017). Methods: Myeloid/lymphoid, stem/progenitor populations profiling by FACS, bone marrow transplantation assays, transcriptomics and proteomics analyses as well pro-inflammatory cytokine profiling and histopathology analyses were performed on the transgenic Abi-1KO mice carrying bone marrow-selective knockout at 4 weeks post-recombination, upon confirming both inducible inactivation of the Abi1flox allele and loss of Abi-1 protein in the marrow (Fig.1A, B). Results: To better understand initial systemic events that lead to the development of MPN-like disease in aged Abi-1KO mice we have now characterized early changes within the hematopoietic system associated with loss of Abi-1. Blood count analysis indicated leukocytosis, anemia and thrombocytosis, and an increase in the fraction of myeloid (CD11b+/Gr-1+) as well as macrophage/monocyte (F4/80+) cells at the expense of lymphoid (B220+) cells in Abi-1KO relative to Abi-1WT mice (Fig.1C). Previously reported 2.6-fold increase in Abi-1KO LT-HSCs (Chorzalska, ASH 2017) was now shown to be associated with 30% increase in number of LT-HSCs is in the S/G2/M phases of the cell cycle relative to Abi-1WT LT-HSCs (Fig. 1D). Lethally irradiated recipient C57BL/6 wild-type mice transplanted with bone marrow cells from Abi-1KO relative to Abi-1WT mice (in the absence of competitor cells) showed progressive loss of chimerism in primary and secondary recipients (Fig. E). Genome-wide gene expression analysis of Abi-1WT vs. Abi-1KO LSK cells showed significant overexpression of genes regulated by or involved in regulation of the NF-κB pathway (Fig. 1F). Plasma cytokine levels showed 2-fold increase in IL-1B, IL-12, IL-17, IL-23, IL-27, and MCP-1 and nearly 10-fold increase in INFγ (Fig. 1G). Label-free, intensity-based quantitative proteomic analysis of bone marrow from 20-week-old Abi-1KO and Abi-1WT mice showed abundance of peptides derived from Mac-1, myeloperoxidase, STAT1, STAT3, and SFKs - Hck and Fgr, confirming not only activation of SFKs and STAT3 signaling, but also increase in proteins associated with myeloid lineages (Fig. 1H). Loss of bone density (Fig. 1I) and a significant decrease in thymus size (Fig. 1J) were observed in Abi-1KO mice relative to Abi-1WT mice. Conclusions: In sum, phenotypic analyses performed 4-10-weeks post Abi1 gene inactivation indicate changes consistent with accelerated aging of hematopoietic system that are mechanistically linked to inflammatory SFK-STAT3-NF-κB signaling. To our knowledge this is the first animal model linking accelerated inflammation-driven aging of hematopoietic system to development of an MPN in aged mice. Disclosures Olszewski: Genentech: Research Funding; TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding. Reagan:Pfizer: Research Funding; Alexion: Honoraria; Takeda Oncology: Research Funding.
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Spracklen, Andrew J., Emma M. Thornton-Kolbe, Alison N. Bonner, Alexandru Florea, Peter J. Compton, Rodrigo Fernandez-Gonzalez, and Mark Peifer. "The Crk adapter protein is essential for Drosophila embryogenesis, where it regulates multiple actin-dependent morphogenic events." Molecular Biology of the Cell 30, no. 18 (August 15, 2019): 2399–421. http://dx.doi.org/10.1091/mbc.e19-05-0302.
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Small Src homology domain 2 (SH2) and 3 (SH3) adapter proteins regulate cell fate and behavior by mediating interactions between cell surface receptors and downstream signaling effectors in many signal transduction pathways. The CT10 regulator of kinase (Crk) family has tissue-specific roles in phagocytosis, cell migration, and neuronal development and mediates oncogenic signaling in pathways like that of Abelson kinase. However, redundancy among the two mammalian family members and the position of the Drosophila gene on the fourth chromosome precluded assessment of Crk’s full role in embryogenesis. We circumvented these limitations with short hairpin RNA and CRISPR technology to assess Crk’s function in Drosophila morphogenesis. We found that Crk is essential beginning in the first few hours of development, where it ensures accurate mitosis by regulating orchestrated dynamics of the actin cytoskeleton to keep mitotic spindles in syncytial embryos from colliding. In this role, it positively regulates cortical localization of the actin-related protein 2/3 complex (Arp2/3), its regulator suppressor of cAMP receptor (SCAR), and filamentous actin to actin caps and pseudocleavage furrows. Crk loss leads to the loss of nuclei and formation of multinucleate cells. We also found roles for Crk in embryonic wound healing and in axon patterning in the nervous system, where it localizes to the axons and midline glia. Thus, Crk regulates diverse events in embryogenesis that require orchestrated cytoskeletal dynamics.
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Freed, E., and T. Hunter. "A 41-kilodalton protein is a potential substrate for the p210bcr-abl protein-tyrosine kinase in chronic myelogenous leukemia cells." Molecular and Cellular Biology 12, no. 3 (March 1992): 1312–23. http://dx.doi.org/10.1128/mcb.12.3.1312-1323.1992.
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Chronic myelogenous leukemia (CML) is characterized by a translocation involving the c-abl protein-tyrosine kinase gene. A chimeric mRNA is formed containing sequences from a chromosome 22 gene (bcr) at its 5' end and all but the variable exon 1 of c-abl sequence. The product of this mRNA, p210bcr-abl, has constitutively high protein-tyrosine kinase activity. We examined K562 cells and other lines established from CML patients for the presence of phosphotyrosine (P-Tyr)-containing proteins which might be p210bcr-abl substrates. Two-dimensional gel separation of 32P-labeled proteins followed by phosphoamino acid analysis of 25 phosphoproteins, which comprised the major alkali-stable phosphoproteins, indicated that three related proteins of 41 kDa are the most prominent P-Tyr-containing proteins detected by this method. The 41-kDa phosphoproteins are found in two other CML lines that we examined but not in lines of similar lineage isolated from patients with distinct leukemic disease. A protein that comigrates with the major form of pp41 (pp41A) and contains P-Tyr is also found in murine fibroblasts and B-lymphoid cells transformed by Abelson murine leukemia virus, which encodes the v-abl protein, and in platelet-derived growth factor-treated fibroblasts, in which it has been described previously. We analyzed three pairs of Epstein-Barr virus-immortalized B-cell lines from individual CML patients and found that only the lines in which active p210bcr-abl was present contained detectable pp41. We also performed immunoblotting with anti-P-Tyr antibodies on the same CML cell lines and detected at least four other putative substrates of p210bcr-abl, which were undetected with use of the two-dimensional gel technique.
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Freed, E., and T. Hunter. "A 41-kilodalton protein is a potential substrate for the p210bcr-abl protein-tyrosine kinase in chronic myelogenous leukemia cells." Molecular and Cellular Biology 12, no. 3 (March 1992): 1312–23. http://dx.doi.org/10.1128/mcb.12.3.1312.
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Chronic myelogenous leukemia (CML) is characterized by a translocation involving the c-abl protein-tyrosine kinase gene. A chimeric mRNA is formed containing sequences from a chromosome 22 gene (bcr) at its 5' end and all but the variable exon 1 of c-abl sequence. The product of this mRNA, p210bcr-abl, has constitutively high protein-tyrosine kinase activity. We examined K562 cells and other lines established from CML patients for the presence of phosphotyrosine (P-Tyr)-containing proteins which might be p210bcr-abl substrates. Two-dimensional gel separation of 32P-labeled proteins followed by phosphoamino acid analysis of 25 phosphoproteins, which comprised the major alkali-stable phosphoproteins, indicated that three related proteins of 41 kDa are the most prominent P-Tyr-containing proteins detected by this method. The 41-kDa phosphoproteins are found in two other CML lines that we examined but not in lines of similar lineage isolated from patients with distinct leukemic disease. A protein that comigrates with the major form of pp41 (pp41A) and contains P-Tyr is also found in murine fibroblasts and B-lymphoid cells transformed by Abelson murine leukemia virus, which encodes the v-abl protein, and in platelet-derived growth factor-treated fibroblasts, in which it has been described previously. We analyzed three pairs of Epstein-Barr virus-immortalized B-cell lines from individual CML patients and found that only the lines in which active p210bcr-abl was present contained detectable pp41. We also performed immunoblotting with anti-P-Tyr antibodies on the same CML cell lines and detected at least four other putative substrates of p210bcr-abl, which were undetected with use of the two-dimensional gel technique.
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Mi, Tian, Zhengqi Wang, and Kevin Bunting. "The Cooperative Relationship between STAT5 and Reactive Oxygen Species in Leukemia: Mechanism and Therapeutic Potential." Cancers 10, no. 10 (September 27, 2018): 359. http://dx.doi.org/10.3390/cancers10100359.
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Reactive oxygen species (ROS) are now recognized as important second messengers with roles in many aspects of signaling during leukemogenesis. They serve as critical cell signaling molecules that regulate the activity of various enzymes including tyrosine phosphatases. ROS can induce inactivation of tyrosine phosphatases, which counteract the effects of tyrosine kinases. ROS increase phosphorylation of many proteins including signal transducer and activator of transcription-5 (STAT5) via Janus kinases (JAKs). STAT5 is aberrantly activated through phosphorylation in many types of cancer and this constitutive activation is associated with cell survival, proliferation, and self-renewal. Such leukemic activation of STAT5 is rarely caused by mutation of the STAT5 gene itself but instead by overactive mutant receptors with tyrosine kinase activity as well as JAK, SRC family protein tyrosine kinases (SFKs), and Abelson murine leukemia viral oncogene homolog (ABL) kinases. Interestingly, STAT5 suppresses transcription of several genes encoding antioxidant enzymes while simultaneously enhancing transcription of NADPH oxidase. By doing so, STAT5 activation promotes an overall elevation of ROS level, which acts as a feed-forward loop, especially in high risk Fms-related tyrosine kinase 3 (FLT3) mutant leukemia. Therefore, efforts have been made recently to target ROS in cancer cells. Drugs that are able to either quench ROS production or inversely augment ROS-related signaling pathways both have potential as cancer therapies and may afford some selectivity by activating feedback inhibition of the ROS-STAT5 kinome. This review summarizes the cooperative relationship between ROS and STAT5 and explores the pros and cons of emerging ROS-targeting therapies that are selective for leukemia characterized by persistent STAT5 phosphorylation.
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Lee, Sang-Eun, Yoonju Kim, Jeong-Kyu Han, Hoyong Park, Unghwi Lee, Myeongsu Na, Soomin Jeong, ChiHye Chung, Gianluca Cestra, and Sunghoe Chang. "nArgBP2 regulates excitatory synapse formation by controlling dendritic spine morphology." Proceedings of the National Academy of Sciences 113, no. 24 (May 25, 2016): 6749–54. http://dx.doi.org/10.1073/pnas.1600944113.
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Neural Abelson-related gene-binding protein 2 (nArgBP2) was originally identified as a protein that directly interacts with synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3), a postsynaptic scaffolding protein critical for the assembly of glutamatergic synapses. Although genetic deletion of nArgBP2 in mice leads to manic/bipolar-like behaviors resembling many aspects of symptoms in patients with bipolar disorder, the actual function of nArgBP2 at the synapse is completely unknown. Here, we found that the knockdown (KD) of nArgBP2 by specific small hairpin RNAs (shRNAs) resulted in a dramatic change in dendritic spine morphology. Reintroducing shRNA-resistant nArgBP2 reversed these defects. In particular, nArgBP2 KD impaired spine-synapse formation such that excitatory synapses terminated mostly at dendritic shafts instead of spine heads in spiny neurons, although inhibitory synapse formation was not affected. nArgBP2 KD further caused a marked increase of actin cytoskeleton dynamics in spines, which was associated with increased Wiskott–Aldrich syndrome protein-family verprolin homologous protein 1 (WAVE1)/p21-activated kinase (PAK) phosphorylation and reduced activity of cofilin. These effects of nArgBP2 KD in spines were rescued by inhibiting PAK or activating cofilin combined with sequestration of WAVE. Together, our results suggest that nArgBP2 functions to regulate spine morphogenesis and subsequent spine-synapse formation at glutamatergic synapses. They also raise the possibility that the aberrant regulation of synaptic actin filaments caused by reduced nArgBP2 expression may contribute to the manifestation of the synaptic dysfunction observed in manic/bipolar disorder.
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Ravandi, Farhad, Srdan Verstovsek, Zeev Estrov, Jan A. Burger, Solly George, Carol Bivins, Jorge Cortes-Franco, William M. Garrett, Robert C. Newton, and Hagop Kantarjian. "Significant Activity of the JAK2 Inhibitor, INCB018424 in Patients with Secondary, Post-Myeloproliferative Disorder (MPD) Acute Myeloid Leukemia (sAML): Results of An Exploratory Phase II Study." Blood 114, no. 22 (November 20, 2009): 631. http://dx.doi.org/10.1182/blood.v114.22.631.631.
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Abstract Abstract 631 Background: Mutations of JAK2 gene have been identified in a significant proportion of patients with MPDs with the selective JAK2 inhibitors demonstrating significant activity. Patients with AML following prior MPD (sAML) respond poorly to standard cytotoxic chemotherapy and have a poor outcome. Abnormalities of the Jak-Stat signaling pathway have also been identified in a number of other hematological malignancies; chromosomal translocations resulting in TEL-JAK2 constructs lead to the constitutive activation of STAT5, IL-3-independent cellular proliferation, and leukemogenesis. Similarly, infection with oncogenic viruses such as human T-cell lymphotrophic virus, type I, and Abelson murine leukemia viruses results in enhanced kinase activity of Jaks, possibly accounting for their leukemogenic potential. Furthermore, disrupted Jak-Stat signaling has been reported in a number of leukemias. Aim: To identify potential activity of INCB018424 in patients with advanced hematological cancers. Methods: We are conducting a phase II study of INCB018424 in patients with relapsed/refractory leukemias for which no standard therapies are anticipated to result in a durable remission. Patients with performance status 0,1,and 2 with adequate organ function and no active, uncontrolled intercurrent illness or infection receive INCB018424 orally at 25 mg BID daily for 4 weeks (cycle #1). Response is assessed after 2 cycles of treatment. Responding patients or patients with stable disease are allowed to continue until progression. Predetermined dose modifications to 15 mg or 10 mg BID are allowed for drug related toxicities. Results: Eighteen patients [median age, 68 years; (range, 53-88] with relapsed and refractory leukemias (9 de novo AML, 3 sAML, 2 ALL, 1 MDS, 2 CMML, 1 CML) have been treated. The median number of prior therapies is 2 (range,1 to 6). Five patients (1 with AML, 2 with sAML, and 3 with CMML) had the JAK2 V617F mutation. Cytogenetic abnormalities include diploid in 7, chromosome 5 and 7 in 5, t(2;9) in 1, and the Philadelphia chromosome in 2. Pts have received a median of 1 cycle of therapy (range, 1-5 cycles) with 8 pts having stable disease (3 for 2 cycles, 2 for 3 cycles, 1 for 4 cycles, and 2 for 5 cycles). Three patients (including 2 with sAML and 1 with CMML, all with JAK2 mutation) have had significant declines in their bone marrow blasts (to <5%) associated with significant decrease in the size of the spleen and clinical improvement. The regimen has been very well tolerated with only grade 3 side effects being elevation of liver enzymes in 2 patients (thought not to be related to the study drug) and grade 3 thrombocytopenia in 1 patient. Conclusion: INCB018424 has significant activity in sAML and CMML associated with JAK2 V617F mutation. Clinical studies combining it with chemotherapy in sAML are warranted. Disclosures: Ravandi: Incyte Corporation: Research Funding. Verstovsek:Incyte: Research Funding. Garrett:Incyte Corporation: Employment. Newton:Incyte Corporation: Employment.
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Chendamarai, Ezhilarasi, Kavitha M. Lakshmi, Auro Viswabandya, Alok Srivastava, Mammen Chandy, and Vikram Mathews. "Kinetics of Molecular Response among Newly Diagnosed Patients with PML-RARα+ Acute Promyelocytic Leukemia Treated with Arsenic Trioxide." Blood 110, no. 11 (November 16, 2007): 4366. http://dx.doi.org/10.1182/blood.v110.11.4366.4366.
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Abstract Arsenic trioxide (ATO) is an effective agent to induce molecular remission in patients with PML-RARα+ acute promelocytic leukemia (APL). ATO can induce molecular remission in majority of newly diagnosed and relapsed cases. However, there is limited data on the kinetics of this molecular response. From August 2006, fifteen consecutive newly diagnosed cases of APL treated with single agent ATO were serially monitored by real time PCR (RQ PCR) for PML-RARα expression. ATO was initially administered to induce remission for a maximum period of 60 days; this was followed by a 4 week interval and a consolidation course of ATO administered for 4 weeks. Subsequently after second 4 week interval, ATO was administered for 10 days / month for 6 months as a maintenance regimen. Peripheral blood RQ PCR was done at diagnosis, week 1, 2 and 4 and end of induction, onset of consolidation and at end of consolidation. RQ PCR was done using standard primers, probes, conditions and reagents as defined in the EAC program (Leukemia2003; 17: 2318–2357). Abelson (ABL) gene was used as a control gene for normalization. The normalized copy number (NCN) was defined as ratio of PML-RARα/ABL expressed as a percentage. The median age of the patients was 29 years (range: 10 – 60). There were 8 (53%) males and 7 females. 5 (33.3%) belonged to the low risk (WBC < 5 x 109/L and Platelet count >20 x 109/Lt) as defined previously by our group for this regimen. 9 (60%) had the bcr1 isoform and the rest (n=6) had the bcr3 isoform. At diagnosis the median copy number was 5.27% (range: 1.47 – 54). A pattern of increased NCN was noted in the first two weeks in 9 (60%) patients (0.5 – 1.5 log increase) (Illustrated in Figure 1). It is possible that this could be related to the differentiation activity of ATO and the resulting hyperleucocytosis. However, this did not statistically correlate with the WBC count at the same time periods. All patients achieved complete molecular remission. 5 (33.3%) had undetectable levels of PML-RARα by the end of induction, 8 (53%) achieved this by onset of consolidation while 2 (13%) achieved this at the end of consolidation. None of these patients relapsed or died during the follow up period. There did not appear to be any correlation with the pattern of RQ PCR response and age, sex, risk status at diagnosis, bcr isoform and genetic polymorphisms among panel of genes known to be important for ATO biotransformation (GST A1, GST P1, GST M1, GST T1, MTHFR C677T, MTHFR A1298C). In comparison to reported data (Chomienne et al. Leukemia2000; 14: 324–328) the kinetics and quality of molecular response following treatment with ATO is superior to that achieved with conventional ATRA based chemotherapy regimens. Kinetic data of molecular response in a large number of patients would help establish a molecular risk stratification strategy as early predictors of long term responses. Serial RQ PCR n=15: Median ± SD Serial RQ PCR n=15: Median ± SD
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Roberts, Kathryn G., Yung-Li Yang, Debbie Payne-Turner, Richard C. Harvey, I.-Ming Chen, Shalini C. Reshmi, Gastier-Foster Julie, et al. "Functional Analysis of Kinase-Activating Fusions in Ph-like Acute Lymphoblastic Leukemia." Blood 124, no. 21 (December 6, 2014): 786. http://dx.doi.org/10.1182/blood.v124.21.786.786.
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Abstract Introduction: Ph-like or BCR-ABL1-like B-progenitor acute lymphoblastic leukemia (ALL) is a high-risk subtype characterized by a gene expression profile similar to BCR-ABL1 ALL. The prevalence of Ph-like ALL rises from 10% in standard risk childhood ALL to over 25% in young adults. Next-generation sequencing of Ph-like ALL identified a variety of alterations involving kinase or cytokine receptor genes, including rearrangement, sequence mutation and copy number alterations. Chromosomal rearrangements in about one-third of Ph-like ALL cases create fusion genes of a variety of 5’ partners that involve ABL1-class genes (ABL1, ABL2, CSF1R and PDGFRB) or activate JAK family members (JAK2, TYK2, IL2RB) that are potentially amenable to treatment with ABL1-class or JAK-class tyrosine kinase inhibitors (TKIs). Notably, ABL2 (Abelson-related gene, ARG), a homolog of ABL1, has rarely been identified as a rearrangement partner in ALL. CSF1R (encoding the macrophage colony stimulating receptor) regulates the differentiation of macrophages, and is not normally expressed in lymphocytes. Likewise, rearrangements involving the JAK family member TYK2, the beta chain of the interleukin 2 cytokine receptor (IL2RB), and the neurotrophic tyrosine kinase receptor type 3 (NTRK3), have not been previously described in leukemia. The goals of this study were to assess the role of these kinase alterations in leukemogenesis, to determine the activation of signaling pathways, and to investigate the efficacy of TKIs. Methods: Kinase fusions were expressed in interleukin-3 dependent Ba/F3 cells, and co-expressed with the dominant negative isoform of IKAROS (IK6) in interleukin-7 dependent Arf-/- mouse pre-B cells. Xenograft models of 10 Ph-like ALL tumors - ETV6-ABL1, RANBP2-ABL1, PAG1-ABL2, RCSD1-ABL2, SSBP2-CSF1R, IGH-EPOR, ETV6-NTRK3, ATF7IP-JAK2, PAX5-JAK2 and ZEB2-PDGFRB - were generated by engrafting primary human leukemia cells into NOD-SCID IL2R gamma null (NSG) mice. Activation of kinase signaling was performed using phosphoflow cytometry analysis, and sensitivity to TKIs was assessed ex vivo and in vivo. Results: All kinase fusions (PAG1-ABL2, MYH9-IL2RB, ATF7IP-JAK2, ETV6-NTRK3 or MYB-TYK2) induced cytokine-independent proliferation of Ba/F3 cells. Mice transplanted with Arf-/- pre-B cells co-expressing IK6 and either RCSD1-ABL2 or SSBP2-CSF1R developed pre-B ALL (CD43+, B220+, CD19+, BP-1+ and IgM-) with a median latency of 36 and 40 days respectively, providing evidence that ABL2 and CSF1R fusions contribute to leukemogenesis. In human leukemic cells harvested from xenograft mice we observed distinct patterns of kinase signaling activation and TKI sensitivity for the different fusions. Xenograft cells expressing ABL1-class kinase fusions showed activation of STAT5 that was inhibited with imatinib or dasatinib. Phosphorylation of CRKL, a known target of ABL1 and ABL2, was only observed in cells expressing ABL1/2 fusions. Cells harboring ATF7IP-JAK2, PAX5-JAK2 or IGH-EPOR showed phosphorylation of STAT5 that was attenuated with the JAK2 inhibitor, ruxolitinib. In contrast, cells expressing ETV6-NTRK3 signaled through the MAPK pathway with constitutive pERK1/2 that was inhibited with the ALK-inhibitor, crizotinib. This TKI response profile was confirmed by cytotoxicity assays in xenograft cells, with ABL1-class fusions being sensitive to dasatinib (IC50 range 1-2nM), whilst cases harboring ATF7IP-JAK2 or EPOR rearrangement uniquely responded to ruxolitinib with IC50 values of 500nM and 850nM respectively. Interestingly, in human leukemic cells harboring the ETV6-NTRK3 fusion we observed selective inhibition with both crizotinib and the FLT3 inhibitor, lestaurtinib. Pre-clinical studies on three xenograft models of Ph-like ALL - ETV6-ABL1, RCSD1-ABL2 and SSBP2-CSF1R – showed significantly reduced leukemic burden in dasatinib treated mice (20mg/kg/day p.o) compared to vehicle treated mice. Conclusions: These data provide important insight on new targets of rearrangement in ALL and describe the first engineered mouse models of Ph-like B-ALL. Functional modeling of these alterations is essential to improve the clinical management of Ph-like ALL by identifying patients with specific genomic lesions at diagnosis and directing them to treatment with appropriate TKIs combined with chemotherapy, analogous to current treatment for BCR-ABL1 B-ALL. Disclosures Hunger: Bristol Myers Squibb: Consultancy.
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Yen, Ryan, Lambert Yue, Steven Pelech, and Xiaoyan Jiang. "Identification of a Highly Deregulated eIF4F Translation Initiation Complex in Drug-Resistant BCR-ABL + Cells By a Phospho-Proteomic Antibody Microarray." Blood 138, Supplement 1 (November 5, 2021): 3583. http://dx.doi.org/10.1182/blood-2021-149185.
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Abstract Protein-tyrosine kinase inhibitors (TKIs) have been effective for treatment of early stages of chronic myeloid leukemia (CML). However, BCR-ABL-dependent resistance mechanisms and TKI-unresponsive quiescent leukemic stem cells (LSCs) can result in drug resistance and disease relapse. We have demonstrated that Abelson helper integration site-1 (AHI-1) is a highly deregulated protein in CML LSCs. It interacts with BCR-ABL through the AHI-1 WD40 domain and with other proteins, like dynamin-2 (DNM2), through its SH3 domain, to enhance leukemic-initiating activities and TKI resistance. To uncover downstream effects of the AHI-1-BCR-ABL-DNM2 complex and its biological role in mediating TKI resistance in CML stem/progenitor cells, an advanced antibody microarray analysis was then used to investigate differences in the proteome and phosphorylation landscape of BCR-ABL + cells co-transduced with wild-type Ahi-1 or Ahi-1 SH3 Δ mutant in the presence or absence of imatinib (IM). The microarray simultaneously quantified the differences in expression and phosphorylation sites of proteins in multiple signaling pathways using 1325 antibodies in duplicate measurements, and each microarray analysis was performed in duplicate. Significant changes in antibody signals for protein expression or phosphorylation were determined using limma. This analysis revealed that the overexpression of wild-type Ahi-1 (WT Ahi-1) has a profound differential effect, compared to the SH3 domain deleted Ahi-1 (Ahi-1 SH3 Δ), on the expression and phosphorylation status of proteins in BCR-ABL + cells with and without IM treatment. BCR-ABL + cells co-expressing WT Ahi-1 had a greater number of significantly differential antibody signals (7 increases, 42 decreases) when compared to BCR-ABL + cells, while Ahi-1 SH3 Δ expressing cells resulted in fewer significantly differential antibody signals (12 increases, 2 decreases) compared to BCR-ABL + cells. IM treatment resulted in WT Ahi-1 expressing cells having the greatest number of significantly differential antibody signals (7 increases, 56 decreases) compared to BCR-ABL + cells (5 decreases) and those co-expressing Ahi-1 SH3 Δ (2 increases, 9 decreases). Pathway enrichment analysis, using gProfiler, identified that the targets with significantly increased differential antibody signal after IM treatment in WT Ahi-1 cells were related to the regulation of translation initiation complex (p>0.0001). Interestingly, our RNA-seq dataset analysis further identified several members of the eukaryotic initiation factor 4F (eIF4F) complex to be significantly upregulated in CD34 + CML patient cells compared to normal bone marrow, particularly eIF4G1, the scaffold protein of the eIF4F complex involved in translation initiation (2-fold, p=0.001), as well as mTOR, a key regulator that controls the assembly of the eIF4F complex. This finding prompted us to further explore the regulation of translation initiation and the members of the eIF4F complex in BCR-ABL + cells. Immunoblotting demonstrated that BCR-ABL + cells co-transduced with WT Ahi-1 showed increased expression of eIF4G1 (3-fold) and eIF4B (2-fold), a cofactor that regulates the helicase activity of the eIF4F complex, compared to BCR-ABL + cells. Additionally, Cyclin D3, a gene reported to be sensitive to eIF4F translational activity, was found to have slightly increased expression (1.4-fold) in WT Ahi-1 cells compared to BCR-ABL + cells. Most interestingly, these results were also demonstrated in IM-resistant CML cells as compared to IM-sensitive cells, with an increase in eIF4G1 expression (2-fold), phosphorylation of eIF4B (5-fold, p=0.003), and Cyclin D3 expression (4-fold, p<0.05). Mechanistically, eIF4G1 knockdown by shRNA impaired survival (5-fold, p<0.0001) and increases TKI sensitivity in IM-resistant cells (3-fold, p<0.05). A new protein interaction between eIF4G1 and the mRNA cap-binding protein eIF4E was further identified in these cells using a proximity ligation assay. Thus, we have uncovered that the eIF4F complex, the key regulator of the mRNA-ribosome recruitment phase of translation initiation, has increased activity in IM-resistant cells, which may contribute to the regulation of TKI resistance in CML. Disclosures No relevant conflicts of interest to declare.
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Wu, Chengchao, Jin Chen, Yunxia Liu, and Xuehai Hu. "Improved Prediction of Regulatory Element Using Hybrid Abelian Complexity Features with DNA Sequences." International Journal of Molecular Sciences 20, no. 7 (April 5, 2019): 1704. http://dx.doi.org/10.3390/ijms20071704.
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Abstract: Deciphering the code of cis-regulatory element (CRE) is one of the core issues of current biology. As an important category of CRE, enhancers play crucial roles in gene transcriptional regulations in a distant manner. Further, the disruption of an enhancer can cause abnormal transcription and, thus, trigger human diseases, which means that its accurate identification is currently of broad interest. Here, we introduce an innovative concept, i.e., abelian complexity function (ACF), which is a more complex extension of the classic subword complexity function, for a new coding of DNA sequences. After feature selection by an upper bound estimation and integration with DNA composition features, we developed an enhancer prediction model with hybrid abelian complexity features (HACF). Compared with existing methods, HACF shows consistently superior performance on three sources of enhancer datasets. We tested the generalization ability of HACF by scanning human chromosome 22 to validate previously reported super-enhancers. Meanwhile, we identified novel candidate enhancers which have supports from enhancer-related ENCODE ChIP-seq signals. In summary, HACF improves current enhancer prediction and may be beneficial for further prioritization of functional noncoding variants.
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Andersson, Åsa, and Freja Aksel Jacobsen. "B-cells and Inflammation in the Absence of the Abelson Related Gene (Arg)." Journal of Clinical & Cellular Immunology 07, no. 06 (2016). http://dx.doi.org/10.4172/2155-9899.1000470.
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Li, Zhen, Zhenyue Chen, Xiaotan Wang, Zehui Li, He Sun, Jinqiang Wei, Xianzhong Zeng, Xuewei Cao, and Chao Wan. "Integrated Analysis of miRNAs and Gene Expression Profiles Reveals Potential Biomarkers for Osteoarthritis." Frontiers in Genetics 13 (June 17, 2022). http://dx.doi.org/10.3389/fgene.2022.814645.
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Purpose: Currently, the early diagnosis and treatment of osteoarthritis (OA) remain a challenge. In the present study, we attempted to explore potential biomarkers for the diagnosis and treatment of OA.Methods: The differentially expressed genes (DEGs) were identified based on three mRNA datasets of synovial tissues for OA patients and normal controls downloaded from the Gene Expression Omnibus (GEO) database. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used for evaluating gene function related categories. Then, miRNA sequencing was performed for differentially expressed miRNAs’ identification. Finally, weighted gene co-expression network analysis (WGCNA) was performed for genes detected by the three mRNA datasets and a competing endogenous RNA (ceRNA) network with DEGs and differentially expressed microRNAs (miRNAs) was constructed for central genes identification. In addition, the relationship between central gene expression and immune infiltration was analyzed, and the candidate agents for OA were predicted based on the Connectivity Map database. Quantitative RT-PCR (qRT-PCR), Western blotting analysis, and immunofluorescent staining were performed to validate the expression levels of differentially expressed miRNAs and differentially expressed target genes in normal and OA tissues and chondrocytes. MiRNA–mRNA network was also validated in chondrocytes in vitro.Results: A total of 259 DEGs and 26 differentially expressed miRNAs were identified, among which 94 miRNA–mRNA interactions were predicted. The brown module in WGCNA was most closely correlated with the clinical traits of OA. After overlapping the brown module genes with miRNA–mRNA pairs, 27 miRNA–mRNA pairs were obtained. A ceRNA network was constructed with 5505 lncRNA–miRNA–mRNA interactions. B-cell translocation gene 2(BTG2), Abelson-related gene (ABL2), and vascular endothelial growth factor A (VEGFA) were identified to be the central genes with good predictive performance, which were significantly correlated with immune cell infiltration in OA, reflected by declined activated dendritic cells (aDCs), and elevated contents of B cells, macrophages, neutrophils, and T helper cells. Anisomycin, MG-132, thapsigargin, and lycorine were predicted to be the potential candidate agents for OA intervention. In vitro, the expression levels of differentially expressed miRNAs and biomarkers identified in the present study were consistent with the results obtained in normal or OA knee cartilage tissues and chondrocytes. Furthermore, BTG2 was identified to be negatively regulated by miR-125a-5p.Conclusion: BTG2, ABL2, and VEGFA can be regarded as potential predictive and treatment biomarkers for OA, which might guide the clinical therapy of OA.
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Chen, Jinyi, Zhuang Kang, Shenglan Li, Can Wang, Xiaohong Zheng, Zehao Cai, Lexin Pan, Feng Chen, and Wenbin Li. "Molecular profile reveals immune-associated markers of medulloblastoma for different subtypes." Frontiers in Immunology 13 (July 28, 2022). http://dx.doi.org/10.3389/fimmu.2022.911260.
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Medulloblastoma, a common pediatric malignant tumor, has been recognized to have four molecular subgroups [wingless (WNT), sonic hedgehog (SHH), group 3, group 4], which are defined by the characteristic gene transcriptomic and DNA methylomic profiles, and has distinct clinical features within each subgroup. The tumor immune microenvironment is integral in tumor initiation and progression and might be associated with therapeutic responses. However, to date, the immune infiltrative landscape of medulloblastoma has not yet been elucidated. Thus, we proposed MethylCIBERSORT to estimate the degree of immune cell infiltration and weighted correlation network analysis (WGCNA) to find modules of highly correlated genes. Synthesizing the hub genes in the protein–protein interaction (PPI) network and modules of the co-expression network, we identify three candidate biomarkers [GRB2-associated-binding protein 1 (GAB1), Abelson 1 (ABL1), and CXC motif chemokine receptor type 4 (CXCR4)] via the molecular profiles of medulloblastoma. Given this, we investigated the correlation between these three immune hub genes and immune checkpoint blockade response and the potential of drug prediction further. In addition, this study demonstrated a higher presence of endothelial cells and infiltrating immune cells in Group 3 tumor bulk. The above results will be conducive to better comprehending the immune-related pathogenesis and treatment of medulloblastoma.
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Morawietz, Carolin M., Hicham Houhou, Oliver Puckelwaldt, Laura Hehr, Domenic Dreisbach, Annika Mokosch, Elke Roeb, Martin Roderfeld, Bernhard Spengler, and Simone Haeberlein. "Targeting Kinases in Fasciola hepatica: Anthelminthic Effects and Tissue Distribution of Selected Kinase Inhibitors." Frontiers in Veterinary Science 7 (December 21, 2020). http://dx.doi.org/10.3389/fvets.2020.611270.
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Protein kinases have been discussed as promising druggable targets in various parasitic helminths. New drugs are also needed for control of fascioliasis, a food-borne trematode infection and worldwide spread zoonosis, caused by the liver fluke Fasciola hepatica and related species. In this study, we intended to move protein kinases more into the spotlight of Fasciola drug research and characterized the fasciolicidal activity of two small-molecule inhibitors from human cancer research: the Abelson tyrosine kinase (ABL-TK) inhibitor imatinib and the polo-like 1 (PLK1) inhibitor BI2536. BI2536 reduced viability of 4-week-old immature flukes in vitro, while adult worms showed a blockade of egg production. Together with a significantly higher transcriptional expression of PLK1 in adult compared to immature worms, this argues for a role of PLK1 in fluke reproduction. Both fluke stages expressed ABL1-TK transcripts at similar high levels and were affected by imatinib. To study the uptake kinetic and tissue distribution of imatinib in F. hepatica, we applied matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) for the first time in this parasite. Drug imaging revealed the accumulation of imatinib in different fluke tissues from 20 min to 12 h of exposure. Furthermore, we show that imatinib is metabolized to N-desmethyl imatinib by F. hepatica, a bioactive metabolite also found in humans. Besides the vitellarium, gastrodermal tissue showed strong signal intensities. In situ hybridization demonstrated the gastrodermal presence of abl1 transcripts. Finally, we assessed transcriptional changes of physiologically important genes in imatinib-treated flukes. Moderately increased transcript levels of a gene encoding a multidrug resistance protein were detected, which may reflect an attempt to defend against imatinib. Increased expression levels of the cell cycle dependently expressed histone h2b and of two genes encoding superoxide dismutases (SODs) were also observed. In summary, our pilot study demonstrated cross-stage activity of imatinib but not BI2536 against immature and adult F. hepatica in vitro; a fast incorporation of imatinib within minutes, probably via the oral route; and imatinib-induced expression changes of physiologically relevant genes. We conclude that kinases are worth analyzing in more detail to evaluate the potential as therapeutic targets in F. hepatica.