Novel Approaches to AML Differentiation Therapy

Survival of children with AML remains poor because our treatments haven't changed much in 30 years. AML is a disease of DNA – mutations found in leukemia DNA are not seen in normal blood cells. However, we think that the physical structure of DNA itself could also be important in leukemia development. If the DNA in a cell was stretched out, it would be six feet long, yet it has to be tightly packed to fit inside the head of a pin. When we looked at leukemia under the microscope, the DNA was not as tightly wound as it should be. We suspected that AML might result from problems in DNA packing. We found that one protein often increased in AML cells directly loosens DNA winding. This especially occurs in kids with Down syndrome or in situations where leukemias have extra copies of chromosomes. When the DNA is “unpacked,” the cell loses its ability to develop normally, leading to AML.

Project Goal: In this project, we propose a new idea in leukemia research: AML may result from unwinding of tightly packed DNA. Drugs that reverse this process could offer new treatments. We will use cutting-edge techniques to understand how DNA unpacking promotes leukemia and test if drugs that target DNA packing kill leukemia cells. We hope our work will lead to new clinical trials for children with leukemia, using drugs that are more effective and less toxic than our current therapies.

Project Update 2022: We have made exciting progress on our ALSF project to understand how to target AML via pathways that cause differentiation. The initial goal of our project was to understand why Down syndrome, in which kids have an extra copy of a single chromosome (number 21), causes increased leukemia risk. We found one gene that lives on chromosome 21, called HMGN1, causes blood abnormalities and a higher risk of leukemia in Down syndrome when its level is increased. We tried to understand exactly how HMGN1 does this. HMGN1 is a protein that affects how chromatin (the way DNA is packaged inside cells) is structured. We found that HMGN1 causes bone marrow cells to remain as immature “undifferentiated” stem-like cells, rather than differentiate normally. This predisposes the cells to develop into leukemia. Our experiments have suggested new therapies that can reverse these changes. We published two papers from our ALSF project to date that suggest global changes in regulation of chromatin is how HMGN1 affects blood development (Mowery et al. Cell Reports; Cabal-Hierro et al. Nature Communications). That work also nominated lysine acetyltransferase enzymes as a possible new target for therapies that might overcome the differentiation block characteristic of AML. We have broadened this concept to ask how chromatin regulates differentiation of normal stem cells compared to AML, not only in the context of Down syndrome. We used a new technology called Global Chromatin Profiling by Mass Spectrometry (GCP-MS) to define the chromatin marks that are most highly associated with myeloid differentiation and how they are altered in AML. This has led us to a new set of therapeutic targets for leukemia treatment, a specific family of lysine acetyltransferases that had not been studied before in leukemia. We have exciting new data that inhibition of these enzymes, using drugs or genetics, synergizes with known leukemia drugs to overcome the differentiation block in AML cells. We are excited that these results could lead to new treatments for children with leukemia, even those without Down syndrome, and could also be used to reduce toxicity of conventional chemotherapy regimens by incorporation of targeted differentiation therapies.