Characterization of the hierarchical organisation of MLL leukemias and pharmacological targeting of key signalling pathways and epigenetic enzymes in human MLL leukemia stem cells.

• Applicant: Dr. Jesús Duque-Afonso
• Subject Area: Hematology, Oncology
• Term: from 2011 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 215322340

Balanced chromosomal translocations play an important role in the pathogenesis of leukemias. Chromosomal translocations involving the MLL gene located on chromosome band 11q23 are implicated in childhood and adult leukemias and therapy-related leukemia. These translocations are associated with unique clinical and biological characteristics and lead to pathogenesis of acute leukemias with both lymphoid (ALL) and myeloid (AML) phenotype. Currently, more than 50 MLL fusion partner genes are described. They induce a corrupted transcriptional program including the aberrant expression of homeobox (HOX) related genes and the epigenetic regulation of other MLL target genes through recruitment of chromatin-modifying enzymes, including histone methyltransferases (HMTs) and protein arginine methyltransferases (PRMTs). The cancer stem cell hypothesis suggests that the origin and maintenance of a leukemic clone depends on a rare cell population at the apex of the cellular hierarchy with indefinite potential for self-renewal, the leukemia stem cells (LSCs). Signaling pathways aberrantly activated, including the GSK3- and Wnt/b-catenin-pathway, confer self-renewal, proliferative and anti-apoptotic properties to MLL leukemia cells. The goal of this project is the characterization of the malignant/aberrant hierarchical organisation and signaling properties of LSC subpopulations in primary patient samples and well-characterized MLL leukemia models. LSC frequencies and hierarchical relationships will dynamically be tracked at baseline and in response to pharmacological signaling and epigenetic targeting of MLL LSCs using mass cytometry (CYTOF) and xenotransplantation models. The epigenetic and signaling targeting of MLL leukemia stem cells has clinical implications and will allow the development of clinical therapies to eradicate this cell subpopulation and to improve the prognosis of patients bearing MLL translocations.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Michael Cleary