Insights into cellular and molecular mechanisms of normal and malignant hematopoiesis from mouse models

Acute myeloid leukemia (AML) refers to a group of aggressive rare heterogenous hematological disease that results from clonal transformation of immature hematopoietic progenitors. Leukemic transformation of cells occurs due to the acquisitions of genetic aberrations that confer a proliferative and survival advantage, and diminished hematopoietic differentiation. Identification of key alterations and mechanisms in the epigenetic network leading to cellular transformation and disease progression may provide novel intervention points for therapy.
To better understand the role of the NSD1 H3K36 histone methyltransferase that is recurrently mutated in AML, our lab established conditional KO mice. All Nsd1-/- mice developed a lethal disease mimicking human acute erythroleukemia. By performing several comparative analyses, I was able to show that the activity of the SET-domain of Nsd1 is indispensable for terminal erythroid cell maturation. Our accumulative observations suggest a model where the NSD1 catalytic activity is essential for creating an erythroid promoting genome-wide epigenetic environment that modulates the activity of the GATA1 erythroid transcriptional master regulator (Chapter I).
To study the cellular origin of acute leukemia driven by MLL rearrangements, our lab established an inducible transgenic mouse model. Activation of the MLL-AF9 or MLL-ENL fusions led to fully reversible leukemia phenotype with some phenotypic differences. My work suggested that in contrast to MLL-AF9, the MLL-ENL fusion mostly targets multipotent progenitors leading to leukemia with myeloid and lymphoid characteristics. In addition, MLL-ENL expression level equal or exceeding the wild-type MLL seemed to be critical for leukemic transformation (Chapter II & appendix 1). MLL-fusions driven leukemia originating from hematopoietic stem cells (HSCs) are characterized by elevated expression of the transcription factors ERG and EVI1. To better understand their role in the disease, I attempted to establish a transgenic fluorescent ERG reporter. Genome editing in zygotes allowed us to establish ERG-2A-YFP mice, however, I never detected the fluorescent signals, most likely due to low expression (Chapter III).
Transgenic mouse models have been extensively used for delineating human underlaying leukemogenic mechanisms and the development of new therapeutic agents. I wrote a review about the various types of AML mouse models generated, and how they helped in our understanding of disease etiology and progression (Appendix 2).