Texas Children's Hospital Archives - Hyundai Hope On Wheels

2019

Scholar Grant

Alison Bertuch

Houston, TX

Title: The Role of DNA Repair Defects in Leukemia Predisposition in the Ribosomopathy Shwachman-Diamond Syndrome

Executive Summary:
Cancer is the greatest threat to life for children with Shwachman-Diamond syndrome (SDS), a genetic disorder that is classically associated with a failure of the bone marrow to produce neutrophils (a class of white blood cells) and a failure of the pancreas to produce digestive enzymes. As many as 1 in 5 children with SDS will be diagnosed with myelodysplastic syndrome (MDS), a type of bone marrow cancer, or acute myeloid leukemia (AML) by the time they are 20 years old. The SBDS protein, which is mutated in children with SDS, plays a critical role in the formation of ribosomes, which are the protein factories of the cell. Why a defect in forming ribosomes or other consequences of SBDS mutation predispose children with SDS to MDS/AML is not known. Although SDS cells acquire mutations in the tumor suppressor gene TP53, additional mutations are likely required to develop MDS/AML.

This proposal seeks to understand the relationship between SBDS and the ability of cells to repair breaks in DNA, with the long-term goal of understanding the contribution of DNA repair defects to the development MDS/AML in SDS. In our research so far, we have found that cell lines derived from children with SDS or cell lines in which we have lowered the level of the SBDS protein are sensitive to radiation treatment. We have also found that cells with lower SBDS levels have a reduced ability to repair DNA breaks using one of the major pathways of repair known as homologous recombination (HR). We have two important clues as to how SBDS impacts HR. First is our finding that a key HR protein, Rad51, is reduced in SDS cells and second is our finding that the SBDS protein is recruited to sites of DNA breaks. These data have led us to three independent hypotheses:
• SBDS influences HR by affecting ribosomes and the synthesis of HR proteins, such as Rad51.
• SBDS influences HR through its interaction with sites of DNA breaks.
• Defects in HR in SDS cells increase the mutation rate, which, when combined with TP53 mutation, could promote MDS and AML.

We will test these hypotheses by completing the following research aims:
• We will determine whether SBDS influences HR through its role in the formation of ribosomes and secondarily the production of HR proteins.
• We will determine whether SBDS influences HR through its interaction with sites of DNA DSBs.
• We will determine if SDS cell lines have a higher rate of mutation accumulation compared to normal cell lines.

Successfully completing the proposed research will move the field of pediatric cancer forward by uncovering the mechanism by which the mutation of a single protein (SBDS) can have a major impact on an essential function (HR) and may contribute to predisposition to MDS and AML. While focused on SDS, we anticipate the results may inform other cancer predisposition syndromes in which ribosome synthesis is altered as well as pediatric cancers in which ribosomes are perturbed.

2019

Young Investigator

Sarah Injac

Houston, TX

Executive Summary: Medulloblastoma (MB) is the most common malignant brain tumor of childhood. While it is most often diagnosed as an isolated mass, MB is an aggressive tumor, and a substantial minority of patients have disease that has already spread at diagnosis. The current standard therapy for MB results in cure rates of approximately 75%. However, the outcomes remain dismal for patients whose tumors fail to respond to initial therapy and patients who have disease that recurs following treatment. There are currently no effective second line therapies for relapsed or refractory disease. In addition, many long-term survivors of childhood MB face significant treatment-related side effects. New therapies, therefore, remain urgently needed.

We recently reported an approach in which we used available molecular information to identify drugs already in clinical use that have the potential to be repurposed for the treatment of MB. Using this approach, we identified a heart medication, digoxin, which significantly prolongs survival in mouse models of Group 3 MB (the MB sub-type with the worst outcomes). Our subsequent studies showed that the transcription factor, LHX9, was the gene most downregulated in response to digoxin treatment in a model of Group 3 disease. LHX9 has been proposed to be a core transcription factor in defining the identity of Group 3 tumors; however, this has never been experimentally tested. In this study, we will examine the role of LHX9 in Group 3 MB and test the idea that LHX9 represents a potential novel therapeutic target that is required for tumor growth. To do this we will:
1) Test the requirement of LHX9 for tumor growth in Group 3 MB
2) Evaluate the ability of LHX9 to accelerate tumor cell proliferation and metastasis in Group 3 MB
3) Delineate the mechanisms of LHX9 over-expression and its downstream effects in Group 3 MB