Characterization of the hierarchical organisation of MLL leukemias and pharmacological targeting of key signalling pathways and epigenetic enzymes in human MLL leukemia stem cells.
Final Report Abstract
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. Signaling pathways aberrantly activated confer self-renewal, proliferative and anti-apoptotic properties to MLL leukemia cells. Through functional and comparative genomic studies, an essential role for NF-kB signaling was identified in MLL leukemia. Lipopolysaccharide (LPS) stimulation induced NFkB p65 phosphorylation in MLL leukemia cell lines compared to non-MLL cell lines and was blocked by IKK inhibition. MLL leukemia cells are highly responsive to NF-kB upstream activation and dependent on pathway signaling. The genetic diversity and low incidence of acute lymphoblastic leukemia (ALL) serve as major barriers to investigations of their molecular pathogenesis and translational biology. To address this, we have developed novel mouse strains that conditionally activate and express E2A-PBX1 from the chromosomal translocation t(1;19), present in 5-7% of pediatric ALL. We used our conditional E2A-PBX1 mouse model to study ALL pathogenesis and to test novel targeted therapies. Whole exome sequencing detected secondary genetic aberrations including deletions of Pax5, which are present in ~45% of pediatric ALLs with E2A-PBX1 gene fusions. Conditional deletion of Pax5 in mice cooperates with E2A-PBX1 increasing the penetrance and shortening the latency of leukemia, providing the first evidence for cooperative oncogenic effects of Pax5 haplo-insufficiency. Secondary recurrent activating mutations were detected in key signaling pathways such as Ras/Mapk and Jak/Stat on which the leukemia cells are strongly dependent. The JAK1/2 inhibitor ruxolitinib blocked the induction of pSTAT5 by IL-7, inhibited colony formation in vitro, and increased disease-free survival in vivo. In summary, the conditional E2A-PBX1 mouse model provides experimental validation of the multistep pathogenesis for a subset of ALL previously inferred from genomic analyses and provides a platform for comparative mechanistic and preclinical studies.
Publications
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Epigenetic modifications mediated by the AML1/ETO and MLL leukemia fusion proteins. In: Lübbert M., Jones P. (eds) Epigenetic Therapy of Cancer. Springer, Berlin, Heidelberg, 2014. ISBN: 978-3-642-38403-5 (Print) 978-3-642-38404-2 (Online). S. 121-144
Duque-Afonso, Jesús; Lübbert, Michael & Cleary, Michael L.
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Epigenetic roles of MLL oncoproteins are dependent on NF-κB. Cancer Cell. 2013; 24(4):423-37
Kuo HP, Wang Z, Lee DF, Iwasaki M, Duque-Afonso J, Wong SH, Lin CH, Figueroa ME, Su J, Lemischka IR, Cleary ML
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Comparative studies of B cell precursor ALL pathogenesis and translational biology using a conditional E2a-PBX1 transgenic mouse model. ASH Meeting 2014. Abstract and Program book, Abstract #283
Duque-Afonso J, Feng J, Scherer F, Wang Z, Cleary ML
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The AML Salad Bowl. Cancer Cell. 2014;25(3):265-7
Duque-Afonso, Jesús & Cleary, Michael L.
