Publication

Genetic defects in myeloid malignancies and preleukemic conditions

Berger, G., 2019, [Groningen]: Rijksuniversiteit Groningen. 189 p.

Research output: ThesisThesis fully internal (DIV)Academic

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  • Title and contents

    Final publisher's version, 7 MB, PDF document

  • Chapter 1

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  • Chapter 2

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  • Chapter 3

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  • Chapter 4

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  • Chapter 5

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  • Chapter 6

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  • Chapter 7

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  • Chapter 8

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  • Appendices

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  • Complete thesis

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  • Propositions

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  • Gerbrig Berger
Myeloid neoplasms (MNs) are malignant hematopoietic disorders that can be subdivided into acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) based on blast percentage. In recent years, progress has been made in uncovering the landscape of genetic alterations frequently occurring in MNs. This thesis has focused on the impact and consequences of genetic mutations at preleukemic stages. Furthermore, the value of individual aberrancies for the MN phenotype, disease maintenance and response to therapy was investigated.
Therapy-related myeloid neoplasms (t-MNs) are malignant hematopoietic disorders that develop following treatment with chemotherapy and irradiation therapy. Reconstruction based on genetic mutations showed that preleukemic clones can be present years before t-MN diagnosis. Ringsideroblasts (RS) represent an aberrant form of erythroid differentiation which is particularly characteristic for MDS. We demonstrated that the genetic basis for the RS-phenotype in AML is different from MDS, however underlying mechanisms share similarities. MNs containing TP53 mutations are notorious for poor outcomes following chemotherapy. Our data indicate that treatment using hypomethylating agents may be beneficial in AML patients with TP53 mutations. Furthermore, we have demonstrated that genetic predisposition may underlie MN diagnosis in adult cases, which may present as donor cell leukemia. The process of leukemic transformation induced by genetic mutations involves disruption of transcriptional networks. Our observations show that transcriptional co-activator CITED2 is essential for leukemic cell survival in a subset of AML patients.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
Supervisors/Advisors
Award date22-May-2019
Place of Publication[Groningen]
Publisher
Print ISBNs9789403416298
Electronic ISBNs9789403416281
Publication statusPublished - 2019

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