The acute myeloid leukemia associated AML1-ETO fusion protein alters the transcriptome and cellular progression in a single-oncogene expressing in vitro induced pluripotent stem cell based granulocyte differentiation model


Autoři: Esther Tijchon aff001;  Guoqiang Yi aff001;  Amit Mandoli aff001;  Jos G. A. Smits aff001;  Francesco Ferrari aff001;  Branco M. H. Heuts aff001;  Falco Wijnen aff001;  Bowon Kim aff001;  Eva M. Janssen-Megens aff001;  Jan Jacob Schuringa aff002;  Joost H. A. Martens aff001
Působiště autorů: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Nijmegen, the Netherlands aff001;  Department of Hematology, University Medical Centre Groningen, Groningen, The Netherlands aff002
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226435

Souhrn

Acute myeloid leukemia (AML) is characterized by recurrent mutations that affect normal hematopoiesis. The analysis of human AMLs has mostly been performed using end-point materials, such as cell lines and patient derived AMLs that also carry additional contributing mutations. The molecular effects of a single oncogenic hit, such as expression of the AML associated oncoprotein AML1-ETO on hematopoietic development and transformation into a (pre-) leukemic state still needs further investigation. Here we describe the development and characterization of an induced pluripotent stem cell (iPSC) system that allows in vitro differentiation towards different mature myeloid cell types such as monocytes and granulocytes. During in vitro differentiation we expressed the AML1-ETO fusion protein and examined the effects of the oncoprotein on differentiation and the underlying alterations in the gene program at 8 different time points. Our analysis revealed that AML1-ETO as a single oncogenic hit in a non-mutated background blocks granulocytic differentiation, deregulates the gene program via altering the acetylome of the differentiating granulocytic cells, and induces t(8;21) AML associated leukemic characteristics. Together, these results reveal that inducible oncogene expression during in vitro differentiation of iPS cells provides a valuable platform for analysis of aberrant regulation in disease.

Klíčová slova:

Acute myeloid leukemia – Cell differentiation – Flow cytometry – Gene expression – Granulocytes – Induced pluripotent stem cells – Leukemias – Monocytes


Zdroje

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