Hematological Malignancies Program

We conduct comprehensive genome-wide analyses and mechanistic studies of the pathogenesis, clonal evolution and drugs response of multiple HM including acute lymphoblastic and myeloid leukemia, myelodysplasia and bone marrow failure. Our research also identifies the germline determinants of disease susceptibility and drug response as well as explores the biological factors that impact the response to immunotherapy.

Because of the HMP, important scientific advances have been made in identifying the genetic basis of ALL, lineage ambiguous leukemia and pediatric myeloid tumors. Paradigm shifting research, led by HMP-investigators, has shown the importance of phase separation in fusion oncoprotein-driven HM and redefined the molecular classification of pediatric ALL and acute myeloid leukemia (AML). Researchers also integrated primary leukemic cell drug screening (pharmacotyping) into studies on childhood ALL, resulting in the progression of a clinical assay that can guide therapy in future clinical trials.

Conventional chemotherapy agents along with novel targeted and immunotherapeutic agents can result in both short- and long-term drug toxicity. Members of the HMP are designing and implementing studies that are identifying genetic and non-genetic risk factors for drug toxicity in HM. 

Glucocorticoid-induced osteonecrosis, asparaginase toxicities, cytotoxicity of methotrexate and -mercaptopurine and CEP72-mediated vincristine neuropathy are just some of the treatment-related toxicities that impact overall health and complicate treatment strategies. Members of the HMP use genome-wide association studies, pharmacodynamics and chemical screens, among other cutting-edge methodologies, to identify key genetic variations driving toxicities. Data generated in basic research studies and preclinical studies have provided investigators with promising strategies for circumventing toxicities while maintaining cure rates. Research under the HMP umbrella is being translated into promising clinical trials for our patients. 

The HMP is at the forefront of translating genomic breakthroughs into precision medicine strategies for pediatric clinical trials. HMP members have defined the central nervous system (CNS) leukemia status to guide risk-directed early intensive intrathecal therapy, successfully eliminating CNS irradiation for all patients with ALL. This finding influenced several study groups to adopt our paradigm-shifting practice. Additionally, HMP members pioneered the use of measurable residual disease (MRD) assessment for risk-adapted systemic treatment, improving overall survival to over 90% for the first time. Our clinical trial also led to landmark advancements, including the first randomized study demonstrating that dasatinib provided superior CNS control and event-free survival in pediatric patients with BCR::ABL-positive ALL. Moreover, we have translated a multitude of pivotal laboratory discoveries into innovative precision medicine initiatives. HMP researchers employ pharmacotyping to conduct preclinical testing, identify biomarker using genomic, flow cytometric and MRD approaches and advance novel immunotherapeutic approaches. This comprehensive multifaceted approach has resulted in multiple new cellular and immunotherapy approaches to significantly improve treatment outcomes for patients with high-risk HM. 

Pediatric cancers generally show limited variation in incidence or outcomes across patient populations, but exceptions exist, notably in pediatric ALL. HMP investigators have identified differences in incidence, genomic features, treatment outcomes and therapy-related toxicities among patients with leukemia. The HMP is dedicated to identifying risk variants for pediatric HM and developing risk-directed treatments to achieve comparable outcomes between all patient populations.