Ph.D., Joint program of Massachusetts Institute of Technology and National University of Singapore, 2013
|My research group focuses on normal and malignant hematopoietic stem and progenitor cells, specifically early erythroid progenitors and leukemic stem cells. We are currently using both CRISPR/Cas functional genomic and forward chemical biology genetic approaches to uncover critical genes and small chemical compounds regulating the self-renewal of hematopoietic stem and progenitor cells. The ultimate goal of this work is to identify novel therapeutics for drug resistant cancer-related anemias and leukemias through targeting of novel self-renewal pathways and metabolic vulnerabilities.|
Stem and progenitor cells of many adult lineages undergo self-renewal. Exploiting self-renewal mechanisms holds great promise for the development of cell-based and regenerative medical strategies and for prevention of the abnormal activation of self-renewal pathways that contribute to irregular cell proliferation and carcinogenesis. Our research centers on normal and malignant progenitor and stem cells in the blood-forming system, specifically early erythroid progenitors and leukemic stem cells.
Thus far, we have utilized reverse genetics to uncover several critical genes regulating early erythroid progenitor self-renewal, a first step towards our understanding of this process. To expand the therapeutic impact of this work, we aim to comprehensively dissect self-renewal pathways to pinpoint potential drug targets, as well as employ high-throughput screening approaches to identify molecules and chemical compounds capable of triggering self-renewal and expansion of these progenitors. These findings will help treat a broad spectrum of unresponsive anemias associated with bone marrow failure disorders, myelodysplastic syndrome, and many major types of cancers.
Our newfound knowledge of self-renewal in normal cells can also be applied to research of leukemic cells, a population of malignant cells whose self-renewal machinery has been hijacked. By identifying the mechanistic divergence between normal and malignant hematopoietic progenitors and stem cells, we seek to specifically inhibit self-renewal in leukemic cells as novel therapies for leukemias.
Zhang, L. and Prak, L. and Rayon-Estrada, V. and Thiru, P. and Flygare, J. and Lim, B. and Lodish, H. F. (2013) ZFP36L2 is required for self-renewal of early burst-forming unit erythroid progenitors. Nature 499(7456) pp. 92-6.
Zhang, L. and Sankaran, V. G. and Lodish, H. F. (2012) MicroRNAs in erythroid and megakaryocytic differentiation and megakaryocyte-erythroid progenitor lineage commitment. Leukemia 26(11) pp. 2310-6.
Hattangadi, S. M. and Wong, P. and Zhang, L. and Flygare, J. and Lodish, H. F. (2011) From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications. Blood 118(24) pp. 6258-68.
Zhang, L. and Flygare, J. and Wong, P. and Lim, B. and Lodish, H. F. (2011) miR-191 regulates mouse erythroblast enucleation by down-regulating Riok3 and Mxi1. Genes Dev 25(2) pp. 119-24.Additional materials of the author at
CSHL Institutional Repository