233 South 10th Street
BLSB 802
Philadelphia, PA 19107
Dr. Jianping Li’s laboratory focuses on translational research in the role of chromatin regulators and immune interaction in blood cancers, especially in the initiation, relapse, and chemotherapy resistance of acute lymphoblastic leukemia and lymphoma. We study aberrant chromatin regulators-driven phenotype and molecular mechanisms using conditional mouse models, patient-derived xenografts (PDXs), and cutting-edge technologies such as CUT&RUN, ChIP-Seq, single-cell RNA-Seq, ATAC-Seq, proteomics, drug screening, flow cytometry and sorting, and CRISPR editing and screening. Based upon the mechanisms, we develop new reversible and targetable treatments to help patients suffering from blood cancers.
Hematopoiesis is the consequence of a dynamic switch of cell-specific gene expression in hematopoietic stem cells (HSCs), guided by chromatin regulators including histone methyltransferases (HMTs) and demethylases (HDMs), histone acetyltransferases (HATs) and deacetylases (HDACs), and chromatin remodeling complexes. These chromatin regulators alter chromatin accessibility and gene expression by regulating the interaction between promoter and enhancer during the self-renewal and differentiation of HSCs. Mutations in chromatin regulators are among the most common in all malignancies, indicating their critical roles in the maintenance of hematopoietic homeostasis. A series of genome sequencing studies revealed that many epigenetic regulators are frequently mutated in blood cancers and exhibit lineage bias. For example, DNMT3A, TET2, ASXL1/2 are most frequently mutated in clonal hematopoiesis of indeterminate potential (CHIP) and myeloid malignancies like myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) while HMTs such as NSD2 (H3K36me2), EZH2 (H3K27me3), and KMT2D (H3K4me1) were recurrently mutated in lymphoid malignancies like acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and lymphoma. These mutations in leukemic stem cells (LSCs) are related to the initiation or the relapse of hematological malignancies. This leads to our hypothesis that mutations of chromatin regulators are both drivers of disease pathogenesis and therapy resistance and relapse. ALL is the most common cancer in children and lymphoma is the most common blood cancer in adults. Our goal is to understand the roles of chromatin regulators in the initiation and relapse of ALL and lymphoma and develop targeted therapies.
Research Projects
Investigate the role of chromatin regulators in the initiation of blood cancers
The mutations of chromatin regulators, frequently identified at the diagnosis, are predicted to be the initiation drivers of blood cancers. These chromatin regulators normally express in HSCs and contribute to the maintenance of hematopoietic homeostasis. Abnormal expression or mutations of them cause aberrant gene expression and lead to blood cancers. Using mouse models, we have been dedicated to understanding how mutations of chromatin regulators impact hematopoiesis and drive the initiation of blood cancers. We previously demonstrated that loss of ASXL2 or truncated mutation of ASXL1 led to myeloid malignancies (Nature Communications 2017; Blood 2018) while mutation of NSD2 caused lymphoid malignancies (Blood, Supplement 1, 2020). We continue to explore the cellular and molecular mechanisms underlying the initiation of ALL and lymphoma driven by chromatin regulator mutations using conditional mouse models and multi-omics technologies (CUT&RUN, ATAC-Seq, and single-cell RNA-Seq).
Elucidate the epigenetic mechanisms underlying the relapse of blood cancers driven by chromatin regulators
Some chromatin regulators are frequently mutated in relapsed ALL and lymphoma, suggesting a correlation with chemotherapy resistance or tumor shelter in other tissues like the central nervous system (CNS). Due to dysregulated function, chromatin regulators drive oncogenic reprogramming and change the phenotype to the relapse state. This requires us to elucidate the aberrant epigenetic landscape underlying the mechanism of relapse of ALL and lymphoma driven by chromatin regulator mutations. We use isogenic CRISPR/Cas9-edited human cell lines, cell line-derived xenograft (CDX), patient-derived xenograft (PDX), conditional mouse models, and multi-omics technologies (CUT&RUN, ChIP-Seq, ATAC-Seq, Hi-C, single-cell RNA-Seq, and proteomics) to determine the mechanisms of chemoresistance and CNS infiltration in ALL and lymphoma (Cancer Discovery, 2022).
Develop target therapies for the initiation and relapse of blood cancers driven by chromatin regulators
Aberrant chromatin regulators drive the initiation or relapse of blood cancers. How can we prevent, or reverse blood cancers driven by aberrant chromatin regulators? Specific inhibitors and degraders of chromatin regulators have emerged as attractive therapeutic targets. Based upon the molecular mechanisms, we design and develop target therapies for ALL and lymphoma driven by chromatin regulators in collaboration with other groups. We will test novel therapies against ALL and lymphoma models in our isogenic cell lines in vitro and mouse models (GEMM, CDX, and PDX) in vivo. (Cancer Discovery, 2022; Nature Chemical Biology (accepted)). A major goal of this part will be to transform our research findings into clinical trials and help patients with ALL and lymphoma.