# Mitotic failure in Fanconi anemia: mechanisms and role in carcinogenesis

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $46,610

## Abstract

Abstract
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.

## Key facts

- **NIH application ID:** 10001741
- **Project number:** 3R01HL132921-03S1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** David W Clapp
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $46,610
- **Award type:** 3
- **Project period:** 2020-02-28 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001741

## Citation

> US National Institutes of Health, RePORTER application 10001741, Mitotic failure in Fanconi anemia: mechanisms and role in carcinogenesis (3R01HL132921-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10001741. Licensed CC0.

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