Deciphering the role of MYB in pediatric astrocytomas
A grant of $25,000 was given to Dana-Farber Children's Cancer Institute in January 2016 to fund a portion of this project
Pediatric low-grade astrocytomas (PLGAs) are the most common solid tumors in children. The tumors themselves, and the treatments that we apply to them, can have devastating life-long neurologic consequences for the children who get them. In particular, standard treatments include surgery, radiation, and chemotherapy—all of which can have profound consequences on the health and neurologic state of a child. One approach to improving treatment strategies is to determine which events within the tumor cells lead to their uncontrolled growth, so that we can devise strategies to reverse the effects of these events.
We have engaged in large-scale analyses of PLGAs to identify their causes. Most cancers are caused by mutations in their DNA, which lead them to generate faulty RNA and grow unchecked. We evaluated DNA and RNA genome-wide across a series of 170 PLGAs to identify the most common and most likely causative mutations among these tumors. We found that the second-most common alterations were in the gene MYB. These alterations accounted for 10% of PLGAs. Mutations of MYB are known to cause leukemias, breast cancers, and adenoid cystic carcinomas, but little is understood about the relation to PLGAs.
One of the interesting features of these MYB mutations is that they were complex events that joined MYB to distant regions of the genome. In this way, they alter not only MYB, but also additional sites, and we do not know whether these additional sites also play a role in PLGA formation.
There is good reason to believe that these sites are, in fact, contributing to tumor formation in their own right. One of the sites co-altered with MYB is the gene QKI, which is frequently mutated in adult glioblastomas. Another site is the gene PCDHG1, which is thought to be involved in neural development and whose modification could be contributing to problems in neural development leading to tumor formation. A third site is the gene ESR1, which encodes the estrogen receptor. The estrogen receptor is the most important therapeutic target in breast cancers and we know that mutations of ESR1 contribute to breast cancer progression, but its role in PLGA development or treatment has not been deeply explored. All of these sites could be contributing to PLGA formation in their own right, or by interacting with MYB. This could have important implications for treatment. For example, the finding that the involvement of ESR1 contributed to tumor formation in some PLGAs could suggest that the estrogen receptor inhibitors currently in widespread use for breast cancer might be effective in those PLGAs.
This research will study the effects of these alterations on MYB itself and on the genes to which it has been joined (QKI, PCDHG1 and ESR1). We will generate neural stem cells in which these alterations have been replicated, determine how they affect the growth of these cells, and whether their effects in these cells mimic the changes seen in childrens’ tumors. We will replicate the entire alteration, including MYB and its partner gene, as well as parts of the alteration (MYB alone or its partner gene alone), to determine which components contribute substantively to tumor formation. We will look at their effects on growth of cells on the bench and on their ability to form tumors in mice. These are fundamental experiments that are necessary to understand how this class of PLGAs arise, and thereby, guide the development of rational diagnostic and targeted therapeutic strategies.
The $25,000 investment from the Olivia Caldwell Foundation will be used to purchase supplies needed to study these genes in the neural stem cells and also support studies to determine whether these altered stem cells can lead to tumor formation when implanted into models. In addition, these funds will help to support a technician who will spend at least half of his/her time on this project and work with other postdoctoral fellows to complete the work and publish a paper on these findings.
Pediatric low-grade astrocytomas (PLGAs) are the most common solid tumors in children. The tumors themselves, and the treatments that we apply to them, can have devastating life-long neurologic consequences for the children who get them. In particular, standard treatments include surgery, radiation, and chemotherapy—all of which can have profound consequences on the health and neurologic state of a child. One approach to improving treatment strategies is to determine which events within the tumor cells lead to their uncontrolled growth, so that we can devise strategies to reverse the effects of these events.
We have engaged in large-scale analyses of PLGAs to identify their causes. Most cancers are caused by mutations in their DNA, which lead them to generate faulty RNA and grow unchecked. We evaluated DNA and RNA genome-wide across a series of 170 PLGAs to identify the most common and most likely causative mutations among these tumors. We found that the second-most common alterations were in the gene MYB. These alterations accounted for 10% of PLGAs. Mutations of MYB are known to cause leukemias, breast cancers, and adenoid cystic carcinomas, but little is understood about the relation to PLGAs.
One of the interesting features of these MYB mutations is that they were complex events that joined MYB to distant regions of the genome. In this way, they alter not only MYB, but also additional sites, and we do not know whether these additional sites also play a role in PLGA formation.
There is good reason to believe that these sites are, in fact, contributing to tumor formation in their own right. One of the sites co-altered with MYB is the gene QKI, which is frequently mutated in adult glioblastomas. Another site is the gene PCDHG1, which is thought to be involved in neural development and whose modification could be contributing to problems in neural development leading to tumor formation. A third site is the gene ESR1, which encodes the estrogen receptor. The estrogen receptor is the most important therapeutic target in breast cancers and we know that mutations of ESR1 contribute to breast cancer progression, but its role in PLGA development or treatment has not been deeply explored. All of these sites could be contributing to PLGA formation in their own right, or by interacting with MYB. This could have important implications for treatment. For example, the finding that the involvement of ESR1 contributed to tumor formation in some PLGAs could suggest that the estrogen receptor inhibitors currently in widespread use for breast cancer might be effective in those PLGAs.
This research will study the effects of these alterations on MYB itself and on the genes to which it has been joined (QKI, PCDHG1 and ESR1). We will generate neural stem cells in which these alterations have been replicated, determine how they affect the growth of these cells, and whether their effects in these cells mimic the changes seen in childrens’ tumors. We will replicate the entire alteration, including MYB and its partner gene, as well as parts of the alteration (MYB alone or its partner gene alone), to determine which components contribute substantively to tumor formation. We will look at their effects on growth of cells on the bench and on their ability to form tumors in mice. These are fundamental experiments that are necessary to understand how this class of PLGAs arise, and thereby, guide the development of rational diagnostic and targeted therapeutic strategies.
The $25,000 investment from the Olivia Caldwell Foundation will be used to purchase supplies needed to study these genes in the neural stem cells and also support studies to determine whether these altered stem cells can lead to tumor formation when implanted into models. In addition, these funds will help to support a technician who will spend at least half of his/her time on this project and work with other postdoctoral fellows to complete the work and publish a paper on these findings.
