Biallelic mutations in the FA/BRCA genes cause Fanconi anemia (FA), a bone marrow failure syndrome associated with genomic instability and cancer. Individuals with FA suffer from a wide range of clinical manifestations, including high risk of leukemia and other malignancies that cause major lifelong morbidity and mortality. Furthermore, acquired mutations of FA genes occur in acute leukemia and other cancers in non-FA patients, indicating that FA genes protect the general population from cancer. Thus, understanding of the FA genome-housekeeping function is highly significant for health of the general public. In interphase, detection of the DNA damage promotes formation of the multiprotein FA complex that orchestrates the repair of genetic lesions. Our previous work revealed that FA signaling ensures high-fidelity mitotic chromosome segregation through regulating the spindle assembly checkpoint (SAC) and maintaining centrosome structure and function (Nalepa et al, JCI 2013). These findings, together with the work of others, suggest that the genome maintenance role of the FA/BRCA pathway extends beyond interphase to prevent cancer. However, it is not mechanistically clear how disruption of the FA genes impairs the SAC and other stages of mitosis. Furthermore, although we have demonstrated that loss of the most common FA gene, FANCA, enhances both interphase and mitotic errors during human hematopoiesis (Abdul-Sater et al, Exp Hem 2015), it is not known whether faulty division of FA- deficient cells directly contributes to malignant transformation. In preliminary studies, we have conducted a synthetic lethal kinome-wide shRNA screen in FANCA-/- patient-derived primary cells and have identified strong novel candidate pathways that functionally interact with FA signaling during mitosis. Here, we propose to mechanistically dissect these newly found pathways ex vivo and in vivo. Further, we have generated a new genetically modified mouse model of FA to directly determine whether erroneous mitosis promotes leukemogenesis in the FA-deficient background through further genetic impairment of the SAC. Together, our work will provide mechanistic insights into genomic instability and malignant transformation resulting from loss of FA signaling, evaluate defective cell division as a causative factor in FA-/- leukemia, and create a preclinical platform to test personalized therapeutic strategies against FA-/- cancers in future studies.
We propose a novel approach to determine how loss of Fanconi anemia (FA) genes enables faulty cell division. We will directly evaluate how impaired division contributes to FA-associated genomic instability and leukemia using a new mouse model we had generated. These studies will help us understand how cancers arise in children with Fanconi anemia and in the general population, and facilitate future personalized anti-cancer therapies.
| Nalepa, Grzegorz; Clapp, D Wade (2018) Fanconi anaemia and cancer: an intricate relationship. Nat Rev Cancer 18:168-185 |
