Determinants of leukemic stem cell origin and function
Final Report Abstract
The goal of these research projects was to elucidate how leukemic stem cells (LSCs) arise and what determines their abnormal function. A number of Hox transcription factors and NUP-Hox fusions have been described in the laboratory of R. Keith Humphries to enhance the self-renewal of hematopoietic stem cells as well as induce leukemias in combination with Meis1. I capitalized on this model to map which hematopoietic cell can be transformed by the fusion gene NUP98-HoxA10hd and Meis1 and could show that even cell types without an intrinsic ability to self-renew – such as common myeloid progenitors – can be transformed, emphasizing the importance of a reactivation of a self-renewal program for the transformation of committed progenitors. In a separate project we demonstrated that BAALC, a well-known predictive factor in AML, has an impact on leukemic transformation by blocking myeloid differentiation and promoting leukemogenesis, but only when combined with the self-renewal promoting oncogene Hoxa9. Mutations in the polycomb-group gene EZH2, an important regulator of Hox gene expression, were recently identified at the Michael Smith Genome Sciences Centre in Vancouver. As these generated considerable interest my main project during the second half of my postdoctoral fellowship focused on functionally characterising these mutations. In a collaborative effort, we could show that the EZH2 mutations found in lymphoma are gain-of-function mutations. We have also generated a novel lymphoma mouse model based on the transgenic expression of mutant EZH2 in combination with Myc. This model demonstrates functionally that EZH2 mutations are oncogenic driver mutations. In ongoing work this new murine lymphoma model now provides a powerful tool to study global changes in the epigenome caused by the frequent EZH2 mutations. Furthermore, this model may be a useful system to test novel treatments aimed at these mutations.
Publications
- Comprehensive microRNA expression profiling of the hematopoietic hierarchy. Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15443-8
Petriv OI, Kuchenbauer F, Delaney AD, Lecault V, White A, Kent D, Marmolejo L, Heuser M, Berg T, Copley M, Ruschmann J, Sekulovic S, Benz C, Kuroda E, Ho V, Antignano F, Halim T, Giambra V, Krystal G, Takei CJ, Weng AP, Piret J, Eaves C, Marra MA, Humphries RK, Hansen CL
- Delineating domains and functions of NUP98 contributing to the leukemogenic activity of NUP98-HOX fusions. Leuk Res. 2010 Dec 2
Yung E, Sekulovic S, Argiropoulos B, Lai CK, Leung M, Berg T, Vollett S, Chang VC, Wan A, Wong S, Humphries RK
- Extrinsic signals determine myeloid-erythroid lineage switch in MN1 leukemia. Exp Hematol. 2010 Mar;38(3):174-9
Heuser M, Park G, Moon Y, Berg T, Xiang P, Kuchenbauer F, Vollett S, Lai C, Humphries RK
- Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood. 2010 Dec 29
Yap DB, Chu J, Berg T, Schapira M, Cheng SW, Moradian A, Morin RD, Mungall AJ, Meissner B, Boyle M, Marquez VE, Marra MA, Gascoyne RD, Humphries RK, Arrowsmith CH, Morin GB, Aparicio SA
- Cell of origin in AML: susceptibility to MN1-induced transformation is regulated by the MEIS1/AbdB-‐like HOX protein complex. Cancer Cell. 2011 Jul 12;20(1):39-52
Heuser M, Yun H, Berg T, Yung E, Argiropoulos B, Kuchenbauer F, Park G, Hamwi I, Palmqvist L, Lai CK, Leung M, Lin G, Chaturvedi A, Thakur BK, Iwasaki M, Bilenky M, Thiessen N, Robertson G, Hirst M, Kent D, Wilson NK, Göttgens B, Eaves C, Cleary ML, Marra M, Ganser A, Humphries RK
- Comprehensive analysis of mammalian miRNA* species and their role in myeloid cells. Blood. 2011 Sep 22;118(12):3350-3358
Kuchenbauer F, Mah S, Heuser M, McPherson AW, Ruschmann J, Rouhi A, Berg T, Bullinger L, Agiropoulos B, Morin RD, Lai D, Starczynowski D, Karsan A, Eaves CJ, Watahiki A, Wang Y, Aparicio SA, Ganser A, Krauter J, Doehner H, Doehner K, Marra MA, Camargo F, Buske C, Humphries RK
- Functional role of BAALC in leukemogenesis. Leukemia. 2011 Aug 26
Heuser M, Berg T, Kuchenbauer F, Lai CK, Park G, Fung S, Lin G, Leung M, Krauter J, Ganser A, Humphries RK
(See online at https://doi.org/10.1038/leu.2011.228)
