Dokument: Einfluss von myeloischen Blasten auf gesunde CD34+ hämatopoietische Stamm- und Progenitorzellen
| Titel: | Einfluss von myeloischen Blasten auf gesunde CD34+ hämatopoietische Stamm- und Progenitorzellen | |||||||
| Weiterer Titel: | Influence of myeloid blasts on healthy CD34+ hematopoietic Stem and progenitor cells | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=49489 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20190506-104410-7 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Jäger, Paul Sebastian [Autor] | |||||||
| Dateien: |
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| Beitragende: | Schroeder, Thomas Michael [Gutachter] PD Dr. med Laws, Hans-Jürgen [Gutachter] | |||||||
| Stichwörter: | AML, Myelosuppression, Pathogenese, hämatopoietische Insuffizienz, hämatopoietische Stamm- und Progenitorzellen, CD34+, TGF-beta, Angiopoietin1 | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Die akute myeloische Leukämie (AML) ist eine heterogene Gruppe maligner Blutstammzellerkrankungen, bei der es zu einer Akkumulation leukämischer Vorläuferzellen im Knochenmark kommt. Die Hauptsymptome der AML sind einer unzureichenden Fähigkeit der gesunden HSPZ geschuldet, eine bedarfsgerechte Blutbildung aufrecht zu halten.
Ging man vor einigen Jahren noch von einer rein räumlichen „Verdrängung“ der gesunden Hämatopoiese durch die klonale Expansion maligner Vorläuferzellen im Knochenmark (KM) aus, weiß man heute, dass dieser Prozess der Myelosuppression deutlich komplexer ist und über verschiedene funktionelle Mechanismen im Knochenmarkmikromilieu abläuft. So konnte unsere Arbeitsgruppe gemeinsam mit anderen zeigen, dass der hämatopoietischen Insuffizienz zum einen eine funktionelle Hemmung sog. mesenchymaler Stromazellen (MSC) zugrunde liegt. Zum anderen legen einige Arbeiten nahe, dass die malignen Zellen auch einen direkten supprimierenden Einfluss auf die gesunden hämatopoietischen Stamm- und Progenitorzellen (HSPZ) ausüben könnten. Um dieser Hypothese in dieser Arbeit experimentell nachzugehen, haben wir die Situation der Knochenmarksinfiltration experimentell nachgestellt. Dazu wurde der Einfluss von mononukleären Zellen (MNC) und CD34+ leukämischen Vorläuferzellen aus dem Knochenmark von 24 neu diagnostizierten AML-Patienten sowie 3 etablierten AML-Zelllinien (HL-60, THP-1, MV4-11) auf gesunde CD34+ HSPZ mittels Zellkulturexperimenten mit konditionierten Medien (CM) untersucht. Hierbei konnten wir zeigen, dass eine Exposition gegenüber den Überständen von AML-Zelllinien und AML-Zellen von Patienten zu einer signifikanten Verringerung der Proliferation von gesunden CD34+ HSPZ und zu einem Zellzyklus-Arrest führten. Darüber hinaus führte eine vorangehende Exposition gegenüber den AML-Zelllinien oder den aus den Patienten gewonnenen AML-Zellen zu einer verminderten Kapazität der gesunden CD34+ HSPZ, Kolonien zu bilden und zu differenzieren. Durch einen Vergleich von 5 gepaarten AML-Patientenproben konnten wir nachweisen, dass diese supprimierende Wirkung auf die gesunde Hämatopoiese durch die CD34+ leukämische Zellpopulation und nicht durch die MNC-Fraktion ausgelöst wurde. Weiterführende qRT-PCR-Analysen zeigten eine signifikante Überexpression verschiedener negativer Regulatoren der Hämatopoiese, wie zum Beispiel TGF-β1 und ANGPT1 in der angereicherten CD34+ Blastenpopulation Zusammengefasst legen diese Daten einen direkten supprimierenden Einfluss der myeloischen Blastenpopulation auf die gesunde CD34+ HSPZ bei AML nahe und stellen somit einen weiteren Mechanismus der Myelosuppression bei der AML dar.Acute myeloid leukemia is a heterogeneous malignant bone marrow disease, which is considered to be clonal stem cell disorder arising from genetic alterations of hematopoietic stem- and progenitor cells (HSPC). Hematopoietic insufficiency is the hallmark of AML with cytopenia-related complications such as bleeding and infections representing the major causes of death. Albeit recent experiment evidence pointed towards an important role of the bone marrow (BM) microenvironment, the underlying mechanisms mediating hematopoietic insufficiency are still poorly understood and therefore often mechanistically summarized as marrow replacement by infiltrating leukemic blasts. Mesenchymal stem- and progenitor cells (MSPC) play an indispensable role for hematopoiesis by regulating and supporting HSPC. It has been reported that MSPC in patients with AML are structurally, genetically and functionally impaired and translated into a significantly diminished ability of those MSC to support CD34+ HSPC. Since the BM of patients with AML is dominated by a leukemic blast population accompanied by a reduction of normal CD34+ hematopoietic stem and progenitor cells (HSPC), we reasoned that leukemic cells might also directly suppress normal HSPC. To experimentally address this hypothesis we modelled the situation of BM infiltration in vitro by exposing healthy BM-derived CD34+ HSPC to supernatants derived from leukemic cells. Conditioned media (CM) were harvested from 3 AML cell lines (THP-1, HL-60, MV4-11) as well as from a total of 24 newly-diagnosed patients with AML covering all relevant WHO subtypes after 3 days of cultivation. Healthy CD34+ HSPC were incubated for 3 days in the presence of leukemic or control media. Subsequently, proliferation, cell cycle behaviour and differentiation of these CD34+ HSPC was investigated using cell counting, dye staining with Ki-67 and Hoechst 33342 as well as semisolid clonogenic assays. Exposure to conditioned media derived from AML cell lines and primary patient samples significantly inhibited proliferation as indicated by a profound reduction of viable healthy CD34+ HSPC. Complementary with this, we observed a clear shift of the cell cycle state of healthy CD34+ HSPC towards a resting phenotype when cultivated in AML-derived media with the majority of cells being in inactive G0 phase. Performing semisolid clonogenic assays demonstrated a strikingly lower colony-forming capacity of CD34+ HSPC following incubation with AML-derived supernatants. These inhibitory effects on healthy hematopoiesis were markedly related to the CD34+ leukemic cell population, but not to the MNC fraction as indicated by a comparison of paired MNC and immunomagnetically enriched CD34+ AML samples. PCR-screening of well-known negative regulators of hematopoiesis revealed a significant overexpression of TGF-β1 and ANGPT1 suggesting a potential role of this candidate molecule for suppression of healthy hematopoiesis by leukemic cells. Overall, these data indicate that leukemic cells mediate direct suppressive effects on important functions of healthy CD34+ HSPC thereby contributing to hematopoietic insufficiency in AML. | |||||||
| Quelle: | Akashi K., et al., A clonogenic common myeloid progenitor that gives rise to all myeloid lineages.
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| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 06.05.2019 | |||||||
| Dateien geändert am: | 06.05.2019 | |||||||
| Promotionsantrag am: | 11.01.2019 | |||||||
| Datum der Promotion: | 25.04.2019 |
