Childhood Cancer

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Investigating phase separated condensates in FPD to MDS/AML progression

Broad Institute
Zuzana Tothova, MD/PhD
Grant Type: 
RUNX1 Early Career Investigator Grants
Year Awarded: 
Type of Childhood Cancer: 
Acute Myeloid Leukemia (AML), Predisposition
Project Description: 

Researchers have made tremendous progress in describing the genetic basis of human blood cancers with the advent of new technologies, such as next generation sequencing (NGS). However, we currently do not understand how most of the genes implicated in leukemia development actually cause leukemia, and how to best target them with new therapies. Inherited mutations or deletions affecting the RUNX1 gene cause a syndrome, Familial Platelet Disorder with predisposition to Acute Myeloid Leukemia (FPD/AML). Patients with RUNX1 FPD have about a 50% lifetime risk of progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) but we currently do not know how to prevent this disease progression. This grant will focus on the interaction between the transcription factor RUNX1 and the cohesin complex subunit STAG2, which is commonly mutated during disease progression from FPD to AML, with the goal to understand how disease progression could be therapeutically targeted. We propose experiments to evaluate the role that RUNX1-containing liquid phase separated droplets 6 play in development of RUNX1 FPD and progression to MDS/AML. Treatment options for patients with RUNX1 FPD are limited, and better understanding of the mechanisms by which leukemia causing genes, such as loss of the second RUNX1 allele or acquisition of mutations in cohesin genes contribute to leukemia development, will inform the design of urgently needed new treatments.