Histone Modification and Hmgn1 Overexpression as Drivers of B-ALL with Polysomy 21
The goal of this project is to discover new treatments for children with B cell acute lymphoblastic leukemia (B-ALL) who have a poor prognosis using current treatment approaches. DNA in human cells is normally divided into 23 chromosomes. In children with B-ALL, the cancer cells can gain extra copies of these chromosomes, most commonly chromosome 21. This suggests that the extra chromosome 21 contributes to how a normal cell becomes leukemia.Supporting this idea, children with Down syndrome are born with an extra copy of chromosome 21 in all of their cells, and they have a 20-fold higher risk of developing B-ALL.
Leukemias that gain extra copies of chromosome 21 are also overrepresented among patients who relapse. At present, we do not have adequate treatments for children with this type of leukemia. Our experiments show that blood cells with an extra chromosome 21 grow more aggressively than those lacking an extra chromosome 21. Our data also shows that specific pathways are turned on in these blood cells.
In this project, we will study the pathways activated in leukemias and blood cells with extra chromosome 21, and test new methods that might specifically stop their growth. This work will identify new ways to treat B-ALL with extra chromosome 21, including for children with Down syndrome. The impact of this project will also extend to patients with other blood cancers, including acute myeloid leukemia (AML), which also frequently has extra copies of chromosome 21.
Andrew Lane answered questions about his research (September 2014):
What were you initially studying with your grant funded by ALSF?
Our goal is to discover new treatment targets for children with poor prognosis leukemias. In this project we wanted to understand the connection between Down syndrome (trisomy of chromosome 21, DS) and acute lymphoblastic leukemia (ALL). Children with DS have at least a 20 times increased risk of developing ALL. But this study may also be relevant to kids without DS: in many cases of pediatric ALL the cancer cells gain an extra copy of chromosome 21, the same extra chromosome that is found in Down syndrome. Also, there is a subset of pediatric ALL with a very poor prognosis that has extra copies of a piece of chromosome 21, called iAMP21 ALL. We studied patient samples with extra copies of chromosome 21 and mice genetically modified to carry extra copies of genes corresponding to human chromosome 21.
What have you found?
B cells with an extra copy of chromosome 21 did not develop normally and behaved like cancer cells in some circumstances. The molecular "signature" of cells with extra copies of chromosome 21 appeared as if they had lost the function of an important enzyme called the polycomb repressor complex. We confirmed this finding in leukemias from several sets of pediatric patients. This led us to try to reverse the signature using drugs called histone demethylase inhibitors. These drugs blocked the growth of cells with extra copies of chromosome 21, suggesting that they might be a useful new therapy in ALL. Finally, we used our mouse model to determine that HMGN1, one of the triplicated genes on chromosome 21, is important for the leukemia predisposition and for generating the unique molecular signature of cells with extra copies of chromosome 21.
What does this mean for children with cancer and their families?
The association between Down syndrome and leukemia has been known for over 80 years, but the basis for that association has been unclear. We also now know that many children without Down syndrome have extra copies of chromosome 21 in their leukemias. Our data suggests that there may be a common signature in these leukemias caused by extra copies of HMGN1 and alterations in function of the polycomb repressor complex. Furthermore, therapies that reverse this signature (like histone demethylase inhibitors) or target HMGN1 could be novel treatments for children with this type of leukemia.
What are your next steps?
We are trying to better understand the molecular basis for how HMGN1 causes abnormal blood cell development, and if HMGN expression is important for survival of leukemia cells. We are also trying to predict if other leukemias without extra copies of chromosome 21 may behave similarly, and therefore might also be susceptible to the same new treatments. Since Down syndrome also causes an increased risk of acute myeloid leukemia (AML), we are asking if HMGN1 is also important for disrupting myeloid cell development and leukemia.
Has this research been published?
Yes, it was published in Nature Genetics in June 2014 (Nat Genet. 2014 Jun;46(6):618-23. doi: 10.1038/ng.2949).
What has this grant from ALSF allowed you to do that you wouldn’t have been able to do otherwise?
The experiments in this project required generation of complex animal models and performance of several next-generation sequencing techniques. These are extremely powerful, yet costly, technologies, and the ALSF support was critical to make the kind of observations that led to our ultimate discoveries.
Why did you choose to work in this field/on this topic?
Despite the remarkable progress in treatments for leukemia in many children, there are still subsets that do poorly like those with amplification of chromosome 21. There are no specific treatments for this group of children. Furthermore, by studying this unique group of leukemias we hope to make discoveries that will enhance our overall understanding of blood cancer biology that may be applicable to a much larger group of patients.
How did you benefit from being mentored during this project; what was most helpful?
Dr. Weinstock is an incredible mentor. He encouraged me to explore a high-risk, high-reward project and opened the full resources of his laboratory to my disposal. He provided just the right amount of support and guidance while allowing me the freedom to ask questions that were most interesting to me. He is also a fantastic model for my career that I will try to emulate as I transition to my own independent research group.
From Dr. Lane's mentor, David Weinstock, MD, regarding the benefits of mentoring:
There were several benefits of mentoring Dr. Lane. First, he made major discoveries into the mechanisms that link Down Syndrome with ALL. Second, he matured into a colleague and future leader in cancer biology. Finally, he was a leader in my laboratory during his fellowship, providing endless assistance to other fellows, students and technicians. The key activities during his fellowship included his work at the research bench, a range of learning and speaking opportunities at conferences and meetings, and his participation in didactic courses at Harvard and the Broad Institute. My role as mentor was to provide guidance and help facilitate these opportunities. Dr. Lane did the rest.