Regulatory pathways driving Ph+ Acute Lymphoblastic Leukemia
Cell Biology
Final Report Abstract
Every day one person in Australia is diagnosed with acute lymphoid leukaemia (ALL). One of the most frequent mutations in ALL is the chromosomal translocation t(9;22)(q34;q11) also known as Philadelphia chromosome (Ph+), resulting in the expression of the BCR-ABL1 chimeric protein and the constitutive activation of the ABL1 kinase. Ph+ ALL patients, particularly adults, have an exceptionally poor prognosis. Hence effective new treatment strategies are required to significantly improve patient outcomes. The overarching aim of this project was to improve the outcome of Ph+ ALL patients characterising the molecular pathogenesis and identifying novel targets for new drug development. Preliminary experiments in our laboratory have identified the transcription factor Erg as a potential driver of Ph+ B-ALL development and maintenance. More precisely, conditional deletion of Erg induces cell death in P190 proB cell lines and Erg haploinsufficiency prevents P190-induced B-ALL development in vivo. Interestingly, when I harnessed those systems neither expression of a cDNA-library containing more than 2 Mio transcripts nor in vivo SB- mutagenesis screens, facilitating SB-activation during early hematopoietic differentiation or at a more lymphoid committed stage, were able to overcome the effects induced by Erg-deletion or Erg-haploinsufficiency respectively. These results reinforce our preliminary data identifying Erg as an important regulator of Ph+ B-ALL. In the second part of this project I aimed to identify novel, Erg-independent regulators of Ph + B-ALL. A mutagenesis screen in P190 (Erg wt/wt) mice identified Myc as a potential driver of the disease. This data was further supported by gene expression profiling data from P190 leukemic cells identifying Myc as well as Erg as strongly upregulated in both murine and human Ph+ B-ALL. Finally, using CRISPR Cas9 technology I was able to show that deletion of either of those two factor delays leukemia development in a humanised mouse model, underlying the critical role of Myc and Erg in human Ph+ B-ALL. In summary, by combining genetic and genomic approach I was able to validate the pivotal role of the transcriptional regulator Erg in Ph+ B-ALL and furthermore identified another critical regulator of the disease: Myc. Currently, studies are underway to translate this data into clinical benefits and improve the outcome for patients suffering from Ph+-B-ALL.
Publications
- (2020) An Erg-driven transcriptional program controls B cell lymphopoiesis. Nature communications 11, 3013
Ng AP, Coughlan HD, Hediyeh-zadeh S, Behrens K et al.
(See online at https://doi.org/10.1038/s41467-020-16828-y)
