Research in Pediatric Hematologic Malignancies
Our highly interactive Department of Pediatric Oncology has a history of research and innovation that has resulted in many of the therapeutics currently used internationally to treat hematologic malignancies, including leukemia and lymphoma. Following these advances, which have improved outcomes for children with cancer, we continue to conduct a high caliber of basic research to identify new treatments and improve therapies for children with hematologic malignancies.
Understanding the Genetic and Epigenetic Determinants of Childhood Leukemias
One of the primary initiatives of our Childhood Hematologic Malignancy Center is the genomic characterization of every newly-diagnosed patient with leukemia.
At the epicenter of this directive is the LEAP consortium Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory, or High Risk Leukemias, applying clinical genomics to pediatric leukemia. Dana-Farber leads a collaborative effort of 15 institutions performing clinical-grade sequencing of newly-diagnosed and relapsed refractory leukemias, then matching those patients to targeted therapies.
Pathogenic variants not previously validated in the literature have been elucidated, and patient derived models (PDX) of these leukemias are investigated via small molecule assay for conferred drug sensitivities. Synthesizing this information, our molecular tumor board — comprising leading researchers in pediatric leukemia — offers specific therapeutic recommendations for each patient based on the mutational signature and drug vulnerabilities demonstrated by their tumor.
Searching for Unique Dependencies in Genetically Defined Leukemias Through Genome-scale Loss-of-Function Screens
Dana-Farber is leading a collaborative effort with Boston Children's Hospital (BCH) and the Broad Institute of MIT and Harvard to generate a pediatric cancer dependency map, the ultimate nexus of translational genomic research with functional data. Applying shRNA and CRISPR-Cas9 screening with high-throughput small-molecule screening against a library of FDA-approved drugs, we identify highly specific targeted therapies.
Novel Targets Emerging From Our Labs
Currently, we have profiled 25 leukemia cell lines with a specific mutational footprint and correlative chemotherapeutic sensitivity. The targets emerging from this data hold tremendous promise for patients with aggressive leukemias that respond poorly to current therapies.
Studying Oncogenic Protein Complexes, Including Fusion Proteins, in Leukemias
Work performed in the Department is defining the mechanisms by which fusion-protein complexes encoded by chromosomal translocations drive abnormal cell proliferation. This discovery generated innovative therapeutic approaches aimed at reversing histone modification mechanisms and preserving chromatin-mediated transcriptional regulation.
Using Multiple Cancer Models, Including Murine and Human Cell Lines, Genetically Engineered Fish and Mice, Human Cell Line Xenografts, and Patient-Derived Xenograft Models
Dana-Farber is home to one of the most comprehensive patient-derived xenograft banks in the United States. We have been adding to that in a more focused way for subsets of leukemia where we do not have good representation for high-risk molecular features. They are used to develop biomarkers of tumor vulnerability to specific drugs and, ultimately, testing of novel therapeutic approaches.
Current Work in Our Labs
The Armstrong Lab is focused on defining the relationship between normal hematopoietic stem/progenitor cells and epigenetic mechanisms of cancer development with a focus on pediatric leukemia.
The Knoechel Lab research focuses on identifying epigenetic dependencies in pediatric tumors with a particular focus on high risk pediatric leukemias.
The Look Lab seeks to elucidate the molecular pathogenesis of human leukemias using cell culture models and a zebrafish animal model.
The Orkin Lab focuses on understanding the regulatory mechanisms operative in stem cells and the development of the blood system that are directly relevant to human cancers.
The Stegmaier Lab focuses on pediatric malignancies notable for aberrancies of differentiation and/or oncogenic activation of transcription factors in an otherwise simple genomic background, such as acute leukemias.