Understanding Leukemia in Children with Down Syndrome to Develop Better Therapies
John Crispino
PhDSt. Jude Children's Research Hospital
Project Term: October 1, 2024 - September 30, 2029
This Specialized Center of Research is focused on identifying the contributions of chromosome 21, which is present in three copies in individuals with Down syndrome (DS), to acute leukemia. Children with DS are at a 20-fold increased risk of leukemia compared to the overall pediatric population and frequently have other health issues that complicate leukemia treatment. Although acute myeloid leukemia in children with DS (ML-DS), which frequently evolves from transient abnormal myelopoiesis (TAM), has a better outcome than acute myeloid leukemia (AML) in children without DS, those who relapse following treatment face an extremely poor prognosis. Similarly, children with DS who develop B-ALL have a worse prognosis than those without DS due to excessive treatment-related mortality and increased risk of relapse. Our overarching, united goal is to develop novel therapies to cure DSassociated leukemias and to reduce the side effects of treatment in this vulnerable population. In addition to children with DS, our study has major implications in other cases of pediatric and adult leukemias. For example, chromosome 21 amplification is one of the most significant gains in several classes of malignancies, including certain subtypes of AML, hyperdiploid ALL, and iAMP21. Amplification of chromosome 21 is also a feature of the acute leukemia phase of a disease named myelofibrosis. Therefore, insights we gain from this research will impact a large group of patients with acute leukemia.
Our Specialized Center of Research is focused on understanding the biology of acute leukemia in children with Down syndrome (DS) and on developing new effective and less toxic treatments. Children with DS have more than a 20-fold increased risk of leukemia, typically at a young age, and the leukemia can either involve myeloid or lymphoid cells. Although children with myeloid leukemia in DS (ML-DS) have a better outcome than children without DS, those with B-cell acute lymphoblastic leukemia in DS (DS-ALL) have a worse outcome.
Our overarching goal is to develop novel therapies to cure both classes of DS-associated leukemias and to reduce the side effects of treatment. Our work is divided into four research programs with overlapping interests.
- Project 1 focuses on identifying factors that promote development of a pre-leukemia in DS named transient abnormal myelopoiesis (TAM). This pre-leukemia is life threatening in many cases and has a high risk of progression to ML-DS. Here, we seek to understand why having three copies of chromosome 21 promotes TAM and ML-DS.
- Project 2 focuses on determining the mechanisms by which a subset of ML-DS cases become resistant to chemotherapy. The team will leverage state of the art techniques to identify the pathways of drug resistance and identify new therapeutic strategies.
- Projects 3 and 4 focus on lymphoid leukemia in children with DS. Project 3 seeks to lay the groundwork for new clinical trials utilizing improved risk stratification and combined kinase inhibition and immunotherapy to improve survival in children with DS-ALL. Project 4 includes basic and translational research to determine how chromosomal rearrangements that lead to increased activity of the CRLF2/TSLP signaling pathway promote leukemia. Alterations inn CRLF2 are seen in more than half of DS-ALL cases as well as in nearly 10% of B-ALL cases in children and young adults without DS.
- The work of these four projects is supported by two cores, including a tissue bank which provides patient samples to the research teams and a bioinformatics and biostatistical core which ensures that our data are analyzed in a comprehensive and rigorous manner.
Our center is composed of the world leaders in leukemia in children with DS and is spread across six countries, and we are actively involved in both basic research and clinical trials. Our expertise and collaborative nature ensure that we will make important advances to curing leukemia in children with Down syndrome.