Synopsis of the current project:
Acute myeloid leukemia (AML) is a somatic genetic disease in which gene mutations or chromosomal translocations accumulate in hematopoietic stem cells thereby disturbing normal blood cell development. AML is extremely difficult to treat, and better treatment options are urgently needed. AML mutations are typically found in a broad range of signaling molecules resulting in aberrant transcriptional programs that drive leukemic transformation. A better understanding of derailed signaling in AML patients is key to developing more effective treatment strategies. Recent findings indicate that transcription is not only a biochemical, but also a biophysical process: spatial localization plays a key role during which all transcriptional components, promoters and enhancers are brought together in so-called transcriptional condensates (TCs), assemblies formed by the propensity of various transcriptional regulators to phase separate at the chromatin. The biophysical process of phase separation is predominantly driven by proteins that are intrinsically disordered (IDPs), i.e., do not have a clear predefined structure. We and others have recently identified that several leukemic oncogenes are also intrinsically disordered and might therefore be initiators of the formation of TCs through phase separation. These exciting observations bring together the biophysical mechanism of phase separation and the cell-biological process of oncogenic transcription. In this proposal two experts with strong complementary expertise in these separate fields join forces to discover how these oncogenic TCs are formed and mis-regulate gene transcription. The overarching aim of this application, using both computational approaches and multi-omics wet lab experimentation, is to develop a comprehensive roadmap of leukemic IDPs, unravel the composition and function of phase separation-controlled leukemic transcriptional condensates, and investigate whether interfering with their function and/or formation will provide alternative treatment strategies for patients with AML. We anticipate that our studies will not only provide important fundamental insights but also provide better therapeutic options for AML patients. For further information please contact: prof.dr. J.J.Schuringa ([email protected]) or prof.dr. P.R. Onck ([email protected]).