Influencia de las anomalías genéticas de buen y mal pronóstico en LLA-B sobre la modulación de las células stem mesenquimales en un modelo in vitro de nicho leucémico

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dc.contributor.advisorVernot, Jean Paul
dc.contributor.authorÁngel Cortés, Santiago
dc.contributor.orcidÁngel Cortés, Santiago [0009-0005-4664-8237]
dc.contributor.researchgroupGrupo de Fisiología Celular y Molecular (FCM)
dc.date.accessioned2026-02-02T20:31:28Z
dc.date.available2026-02-02T20:31:28Z
dc.date.issued2025
dc.descriptionIlustraciones, gráficosspa
dc.description.abstractLas células stem mesenquimales (MSC) de médula ósea (MO) poseen gran relevancia en el establecimiento, desarrollo y progresión de la leucemia linfoide aguda de precursores de células B (LLA-B). Las interacciones de las MSC con las células de LLA-B establecen un nicho leucémico (LN) que modifica las propiedades stem, el secretoma y la expresión génica de las MSC, favoreciendo la proliferación y la quimioresistencia de las células leucémicas. Los subtipos de LLA-B presentan alteraciones genómicas asociadas al desenlace clínico, por ejemplo la fusión ETV6-RUNX1 (t(12;21), de buen pronóstico) o BCR-ABL1 (t(9;22), de mal pronóstico). Sin embargo, se desconoce si estas células con anomalias genéticas distintas alteran diferencialmente las funciones stem o inducen una reprogramación celular particular. En el presente trabajo, se demostró que dos líneas celulares de LLA-B diferentes genéticamente, REH (t(12;21)) y SUP-B15 (t(9;22)), asociadas con un pronóstico favorable y adverso, respectivamente, modulan sus capacidades de proliferación, adhesión y migración durante su interacción con las MSC y, además, alteran diferencialmente el secretoma y las propiedades stem de las MSC durante su interacción. Se destaca que las células SUP-B15 tuvieron una adhesión a las MSC mayor y más rápida, una menor proliferación y una mayor migración hacía CXCL12 que las células REH. Se encontró que el medio condicionado (CM) del LN de SUP-B15 estaba más enriquecido en citoquinas proinflamatorias (en particular IL-6, IL-8 y CCL2) que el del LN de REH. Además, las células SUP-B15 indujeron una mayor adipogénesis en las MSC e interesantemente, preservaron mejor su capacidad de autorrenovación y clonogenicidad, en contraste con las MSC del LN de REH. Se observó que la interacción tanto de SUP-B15 como de REH con las MSC indujo en estas últimas un aumento significativo de la senescencia celular, sin diferencias entre estos subtipos. Adicionalmente, se estudió el impacto de alteraciones mencionadas del secretoma, la senescencia y las propiedades stem de las MSC sobre las propiedades de las células leucémicas, así como la modulación de su quimioresistencia hacía distintos fármacos. Las MSC protegieron de manera significativa a las células SUP-B15 y REH contra tres tratamientos farmacológicos. Los CM de los LN de SUP-B15 y de REH indujeron la senescencia celular de las MSC, pero solo el del LN de SUP-B15 logró consolidar dicha senescencia. También, el tratamiento con las citoquinas más relevantes de estos CM (IL-6, IL-8 y CCL2) indujeron la senescencia de las MSC pero sin alterar la quimioprotección de las MSC. Por otra parte, el tratamiento con IL-6 potenció la autorrenovación de las MSC; además, se evidenció que la inducción de senescencia con IL-6 en las MSC con mayor autorrenovación no afectó su capacidad de quimioprotección, debido a que estas células fueron más eficientes revirtiendo la senescencia. Debido a que las células SUP-B15 indujeron una mayor adipogénesis, se establecieron y evaluaron LN con adipocitos (AD) derivados de MSC. El CM del LN con AD de SUP-B15 expresó más citoquinas proinflamatorias (IL-6, CCL2, MIF y G-CSF) que el LN de REH con AD. De forma interesante, los AD y sus CM protegieron mejor que las MSC a las células SUP-B15, pero no a las REH del efecto citotóxico de los fármacos. Además, los AD también modularon diferencialmente la adhesión y la proliferación, SUP-B15 siendo más adherente y entrando en quiescencia, cambios favorables para la quimioresistencia. En conclusión, la mayor agresividad de las células SUP-B15 se explica de forma multifactorial. Por un lado, durante su interacción con las MSC y los AD presentaron mayor adhesión y modularon de forma dinámica su proliferación y migración; por otro lado, las SUP-B15 reprogramaron a las MSC, generando un LN más adipogénico que, a su vez, favoreció su quimioresistencia contra distintos fármacos. Además, indujeron la senescencia de las MSC sin afectar su capacidad de autorrenovación y clonogenicidad; aumentaron la secreción de citoquinas proinflamatorias, las cuales incrementaron la senescencia, la quimioprotección y la autorrenovación de las MSC. (Texto tomado de la fuente)spa
dc.description.abstractBone marrow (BM) mesenchymal stem cells (MSC) are highly relevant to the development, development, and progression of B-cell acute lymphocytic leukemia (B-ALL). Interactions between MSCs and B-ALL cells establish a leukemic niche (LN) that modifies MSC stem cell properties, secretome, and gene expression, promoting proliferation and chemoresistance. B-ALL subtypes exhibit genomic alterations associated with clinical outcome, such as the ETV6-RUNX1 fusion (t(12;21), favorable prognosis) or BCR-ABL1 fusion (t(9;22), poor prognosis). However, it is unknown whether these genetic abnormalities differentially induce MSC reprogramming and function. In the present work, we demonstrated how two genetically distinct B-ALL cell lines, REH (t(12;21)) and SUP-B15 (t(9;22)), which are also associated with favorable and adverse prognoses, respectively, modulate their proliferation, adhesion, and migration capacities during their interaction with MSC and, in addition, differentially alter the secretome and stem properties of MSC during their interaction. It is notable that SUP-B15 cells had higher and faster adhesion to MSC, lower proliferation, and higher migration toward CXCL12 than REH cells. Furthermore, the conditioned medium (CM) of SUP-B15 LN was found to be more enriched in proinflammatory cytokines (particularly IL-6, IL-8, and CCL2) than that of REH LN. SUP-B15 cells induced greater adipogenesis in MSC and better preserved their self-renewal and clonogenicity capacity, in contrast to MSC from REH LN. It was observed that the interaction of both SUP-B15 and REH with MSC induced a significant increase in cellular senescence in the latter. Additionally, we studied the impact of the aforementioned alterations in the MSC’s secretome and stem functions on the properties of leukemic cells, as well as the modulation of their chemoresistance to different drugs. MSC significantly protected SUP-B15 and REH cells against three drug treatments. CM from SUP-B15 and REH LN induced cellular senescence in MSC, but only the CM from SUP-B15 LN managed to consolidate said senescence. Furthermore, treatment with the most relevant cytokines of these CM (IL-6, IL-8, and CCL2) induced MSC senescence without altering MSC chemoprotection. Treatment with IL-6 enhanced MSC self-renewal; furthermore, it was shown that inducing senescence with IL-6 in MSC with greater self-renewal did not affect their chemoprotection capacity, because these cells were more efficient in reversing senescence. Furthermore, since SUP-B15 cells induced greater adipogenesis, LN with MSC-derived adipocytes (AD) were established, and their secretome, their ability to modulate the properties of B-ALL cells, and their ability to protect them against the cytotoxic effect of different drugs were evaluated. The CM of SUP-B15 LN with AD also expressed more proinflammatory cytokines (IL-6, CCL2, MIF, and G-CSF) than the LNs of REH with AD. Interestingly, AD and their CMs protected SUP-B15 cells, but not REH cells, better than MSC from the drugs’ cytotoxic effects. Furthermore, AD also differentially modulated the proliferation and adhesion of the cell lines, causing SUP-B15 to increase its adhesion and enter a process of cellular quiescence beneficial to its chemoresistance. In conclusion, the greater aggressiveness of SUP-B15 cells was explained by several factors. On one hand, during their interaction with MSC and AD, they exhibited greater adhesion and dynamically modulated their proliferation and migration. On the other hand, they reprogrammed the MSC, generating a more adipogenic LN, which, in turn, favored their chemoresistance against various drugs. Furthermore, they induced MSC senescence without affecting their self-renewal and clonogenicity; they increased the secretion of proinflammatory cytokines, which enhanced MSC senescence, chemoprotection, and self-renewal.eng
dc.description.degreelevelMaestría
dc.description.degreenameMagister en Inmunología
dc.format.extentxix, 113 páginas
dc.format.mimetypeapplication/pdf
dc.identifier.instnameUniversidad Nacional de Colombiaspa
dc.identifier.reponameRepositorio Institucional Universidad Nacional de Colombiaspa
dc.identifier.repourlhttps://repositorio.unal.edu.co/spa
dc.identifier.urihttps://repositorio.unal.edu.co/handle/unal/89367
dc.language.isospa
dc.publisherUniversidad Nacional de Colombia
dc.publisher.branchUniversidad Nacional de Colombia - Sede Bogotá
dc.publisher.facultyFacultad de Medicina
dc.publisher.placeBogotá, Colombia
dc.publisher.programBogotá - Medicina - Maestría en Inmunología
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dc.rights.accessrightsinfo:eu-repo/semantics/openAccess
dc.rights.licenseAtribución-NoComercial 4.0 Internacional
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subject.blaaCélulas madre mesenquimales
dc.subject.ddc610 - Medicina y salud::616 - Enfermedades
dc.subject.ddc610 - Medicina y salud
dc.subject.lembEnvejecimiento celularspa
dc.subject.lembCells - Agingeng
dc.subject.lembLeucemia linfoidespa
dc.subject.lembLymphocytic leukemiaeng
dc.subject.lembMédula óseaspa
dc.subject.lembBone marroweng
dc.subject.lembCitocinasspa
dc.subject.lembCytokineseng
dc.subject.proposalLLA-Bspa
dc.subject.proposalPronóstico favorable y adversospa
dc.subject.proposalMSCspa
dc.subject.proposalNicho leucémicospa
dc.subject.proposalPropiedades stemspa
dc.subject.proposalSenescenciaspa
dc.subject.proposalAdipogénesisspa
dc.subject.proposalQuimioresistenciaspa
dc.subject.proposalB-ALLeng
dc.subject.proposalFavorable and poor prognosiseng
dc.subject.proposalMSCeng
dc.subject.proposalLeukemic nicheeng
dc.subject.proposalStem propertieseng
dc.subject.proposalSenescenceeng
dc.subject.proposalAdipogenesiseng
dc.subject.proposalChemoresistanceeng
dc.titleInfluencia de las anomalías genéticas de buen y mal pronóstico en LLA-B sobre la modulación de las células stem mesenquimales en un modelo in vitro de nicho leucémicospa
dc.title.translatedInfluence of good and poor prognostic genetic abnormalities in B-ALL on the modulation of mesenchymal stem cells in an in vitro model of the leukemic nicheeng
dc.typeTrabajo de grado - Maestría
dc.type.coarhttp://purl.org/coar/resource_type/c_bdcc
dc.type.coarversionhttp://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.contentText
dc.type.driverinfo:eu-repo/semantics/masterThesis
dc.type.redcolhttp://purl.org/redcol/resource_type/TM
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
dcterms.audience.professionaldevelopmentBibliotecarios
dcterms.audience.professionaldevelopmentEstudiantes
dcterms.audience.professionaldevelopmentInvestigadores
dcterms.audience.professionaldevelopmentMaestros
dcterms.audience.professionaldevelopmentPúblico general
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Bloque de licencias

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Nombre:
license.txt
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Maestría en Inmunología