Unveiling the role of PAK2 in CD44 mediated inhibition of proliferation, differentiation and apoptosis in AML cells

dc.contributor.advisorMerzaban, Jasmeen
dc.contributor.authorAldehaiman, Mansour M.
dc.contributor.committeememberMahfouz, Magdy M.
dc.contributor.committeememberArold, Stefan T.
dc.contributor.departmentBiological and Environmental Science and Engineering (BESE) Division
dc.date.accessioned2018-05-24T05:57:11Z
dc.date.available2019-05-23T00:00:00Z
dc.date.issued2018-04
dc.description.abstractAcute myeloid leukemia (AML) is a heterogeneous disease characterized by the accumulation of immature nonfunctional highly proliferative hematopoietic cells in the blood, due to a blockage in myeloid differentiation at various stages. Since the success of the differentiation agent, All-trans retinoic acid (ATRA), in the treatment of acute promyelocytic leukemia (APL), much effort has gone into trying to find agents that are able to differentiate AML cells and specifically the leukemic stem cell (LSC). CD44 is a cell surface receptor that is over-expressed on AML cells. When bound to anti-CD44 monoclonal antibodies (mAbs), this differentiation block is relieved in AML cells and their proliferation is reduced. The molecular mechanisms that AML cells undergo to achieve this reversal of their apparent phenotype is not fully understood. To this end, we designed a study using quantitative phosphoproteomics approaches aimed at identifying differences in phosphorylation found on proteins involved in signaling pathways post-treatment with CD44-mAbs. The Rho family of GTPases emerged as one of the most transformed pathways following the treatment with CD44-mAbs. The P21 activated kinase 2(PAK2), a target of the Rho family of GTPases, was found to be differentially phosphorylated in AML cells post-treatment with CD44-mAbs. This protein has been found to possess a role similar to that of a switch that determines whether the cell survives or undergoes apoptosis. Beyond confirming these results by various biochemical approaches, our study aimed to determine the effect of knock down of PAK2 on AML cell proliferation and differentiation. In addition, over-expression of PAK2 mutants using plasmid cloning was also explored to fully understand how levels of PAK2 as well as the alteration of specific phospohorylation sites could alter AML cell responses to CD44-mAbs. Results from this study will be important in determining whether PAK2 could be used as a potential therapeutic target for AML once its levels are altered.
dc.identifier.citationAldehaiman, M. M. (2018). Unveiling the role of PAK2 in CD44 mediated inhibition of proliferation, differentiation and apoptosis in AML cells. KAUST Research Repository. https://doi.org/10.25781/KAUST-1QR9T
dc.identifier.doi10.25781/KAUST-1QR9T
dc.identifier.urihttp://hdl.handle.net/10754/627947
dc.internal.reviewer-noteORCID email sent to Mansour. - DG
dc.language.isoen
dc.person.id152397
dc.rights.accessrightsAt the time of archiving, the student author of this thesis opted to temporarily restrict access to it. The full text of this thesis became available to the public after the expiration of the embargo on 2019-05-23.
dc.rights.embargodate2019-05-23
dc.subjectLeukemia
dc.subjectAML
dc.subjectAnti-CD44
dc.subjectPAK2
dc.subjectCD44
dc.subjectHL60
dc.titleUnveiling the role of PAK2 in CD44 mediated inhibition of proliferation, differentiation and apoptosis in AML cells
dc.typeThesis
display.details.left<span><h5>Embargo End Date</h5>2019-05-23<br><br><h5>Type</h5>Thesis<br><br><h5>Authors</h5><a href="https://repository.kaust.edu.sa/search?query=orcid.id:0000-0001-7481-9666&spc.sf=dc.date.issued&spc.sd=DESC">Aldehaiman, Mansour M.</a> <a href="https://orcid.org/0000-0001-7481-9666" target="_blank"><img src="https://repository.kaust.edu.sa/server/api/core/bitstreams/82a625b4-ed4b-40c8-865a-d6a5225a26a4/content" width="16" height="16"/></a><br><br><h5>Advisors</h5><a href="https://repository.kaust.edu.sa/search?query=orcid.id:0000-0002-7276-2907&spc.sf=dc.date.issued&spc.sd=DESC">Merzaban, Jasmeen</a> <a href="https://orcid.org/0000-0002-7276-2907" target="_blank"><img src="https://repository.kaust.edu.sa/server/api/core/bitstreams/82a625b4-ed4b-40c8-865a-d6a5225a26a4/content" width="16" height="16"/></a><br><br><h5>Committee Members</h5><a href="https://repository.kaust.edu.sa/search?query=orcid.id:0000-0002-0616-6365&spc.sf=dc.date.issued&spc.sd=DESC">Mahfouz, Magdy M.</a> <a href="https://orcid.org/0000-0002-0616-6365" target="_blank"><img src="https://repository.kaust.edu.sa/server/api/core/bitstreams/82a625b4-ed4b-40c8-865a-d6a5225a26a4/content" width="16" height="16"/></a><br><a href="https://repository.kaust.edu.sa/search?query=orcid.id:0000-0001-5278-0668&spc.sf=dc.date.issued&spc.sd=DESC">Arold, Stefan T.</a> <a href="https://orcid.org/0000-0001-5278-0668" target="_blank"><img src="https://repository.kaust.edu.sa/server/api/core/bitstreams/82a625b4-ed4b-40c8-865a-d6a5225a26a4/content" width="16" height="16"/></a><br><br><h5>Program</h5><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.program=Bioscience,equals">Bioscience</a><br><br><h5>KAUST Department</h5><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.department=Biological and Environmental Science and Engineering (BESE) Division,equals">Biological and Environmental Science and Engineering (BESE) Division</a><br><br><h5>Date</h5>2018-04</span>
display.details.right<span><h5>Access Restrictions</h5>At the time of archiving, the student author of this thesis opted to temporarily restrict access to it. The full text of this thesis became available to the public after the expiration of the embargo on 2019-05-23.<br><br><h5>Abstract</h5>Acute myeloid leukemia (AML) is a heterogeneous disease characterized by the accumulation of immature nonfunctional highly proliferative hematopoietic cells in the blood, due to a blockage in myeloid differentiation at various stages. Since the success of the differentiation agent, All-trans retinoic acid (ATRA), in the treatment of acute promyelocytic leukemia (APL), much effort has gone into trying to find agents that are able to differentiate AML cells and specifically the leukemic stem cell (LSC). CD44 is a cell surface receptor that is over-expressed on AML cells. When bound to anti-CD44 monoclonal antibodies (mAbs), this differentiation block is relieved in AML cells and their proliferation is reduced. The molecular mechanisms that AML cells undergo to achieve this reversal of their apparent phenotype is not fully understood. To this end, we designed a study using quantitative phosphoproteomics approaches aimed at identifying differences in phosphorylation found on proteins involved in signaling pathways post-treatment with CD44-mAbs. The Rho family of GTPases emerged as one of the most transformed pathways following the treatment with CD44-mAbs. The P21 activated kinase 2(PAK2), a target of the Rho family of GTPases, was found to be differentially phosphorylated in AML cells post-treatment with CD44-mAbs. This protein has been found to possess a role similar to that of a switch that determines whether the cell survives or undergoes apoptosis. Beyond confirming these results by various biochemical approaches, our study aimed to determine the effect of knock down of PAK2 on AML cell proliferation and differentiation. In addition, over-expression of PAK2 mutants using plasmid cloning was also explored to fully understand how levels of PAK2 as well as the alteration of specific phospohorylation sites could alter AML cell responses to CD44-mAbs. Results from this study will be important in determining whether PAK2 could be used as a potential therapeutic target for AML once its levels are altered.<br><br><h5>Citation</h5>Aldehaiman, M. M. (2018). Unveiling the role of PAK2 in CD44 mediated inhibition of proliferation, differentiation and apoptosis in AML cells. KAUST Research Repository. https://doi.org/10.25781/KAUST-1QR9T<br><br><h5>DOI</h5><a href="https://doi.org/10.25781/KAUST-1QR9T">10.25781/KAUST-1QR9T</a></span>
orcid.id0000-0001-5278-0668
orcid.id0000-0002-0616-6365
orcid.id0000-0002-7276-2907
orcid.id0000-0001-7481-9666
refterms.dateFOA2019-05-23T00:00:00Z
thesis.degree.disciplineBioscience
thesis.degree.grantorKing Abdullah University of Science and Technology
thesis.degree.nameMaster of Science
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