Lan Wang, Ph.D.
Assistant Professor of Biochemistry and Molecular biology
Description of Research
Dr. Wang’s research focuses on understanding the pathogenesis of hematological malignancies and stem cell studies. In particular, Dr. Wang is interested in identifying the genes that are disrupted in these disorders, and developing the new therapeutic strategies for patients with these diseases. Blood cells are generated by hematopoietic stem cells, which are proposed to be the cell of origin in leukemia and we are studying how their behavior goes awry when the cells become transformed. Cancer stem cells show loss of normal growth control mechanisms, leading to abnormal cell division, survival and expansion. The development of hematological malignancies is commonly associated with aberrant transcriptional regulation, where genes are inappropriately turned on or off. In most cases, correcting these abnormalities would block the development or progression of hematological malignancies in patients.
Dr. Wang began studying the targeted therapy of hematological malignancies in 2002. Dr. Wang investigated the effects of Eriocalyxin B (EriB) on the t(8;21)- leukemia. EriB induced programmed cell death of leukemia cells through damage of mitochondria functions, down-regulation of Bcl-2, and activation of caspase-3. Dr. Wang’s study showed that EriB could cause a caspase-3 dependent degradation of AML1-ETO, and the aspartic acid residue at position 188 of AML1-ETO was the cleavage site. Interestingly, EriB significantly prolonged life span in the murine model of AML. Dr. Wang also discovered that Realgar-Indigo naturalis formula, with tetraarsenic tetrasulfide, indirubin and tanshinone IIA, yields synergy in the treatment of a murine acute promyelocyte leukemia (APL) model and in the induction of cell differentiation through promoting AQP9-mediated transportation of arsenic into cells and intensifing ubiquitination/degradation of PML-RARα.
In Dr. Nimer’s laboratory at Memorial Sloan-Kettering Cancer Center, Dr. Wang’s study suggests that AML1-ETO directly interacts with histone acetyltransferase p300, and that p300 can acetylate two lysine residues in AML1-ETO and AML1-ETO9a in human and mouse leukemia cells. The post-translational acetylation, adding an acetyl group to a specific amino acid in AML1-ETO, is the key to the ability of AML1-ETO to promote self-renewal of hematopoietic stem/progenitor cells. Further, inhibition of this acetylation reduces the growth of cancer cells. The information generated by this study may be useful for developing targeted therapeutics for human leukemia. Dr. Wang is also interested in using murine leukemia models to identify therapeutic targets for leukemia stem cells. AML1-ETO and p300 coopreatively activate the transcription of Id1, and the upregulation of Id1 may promote the development of hematological malignancies. Loss of Id1 abrogates the leukemia progression in mouse models. Therefore, the drugs developed to inhibit Id1 levels may provide new therapies for these diseases.
- EiB could cause a caspase-3 dependent degradation of AML1-ETO, and the aspartic acid residue at position 188 of AML1-ETO was the cleavage site.
- Realgar-Indigo naturalis formula yields synergy in APL treatment and the induction of cell differentiation through promoting AQP9-mediated transportation of arsenic and ubiquitination of PML-RARα.
- The leukemogenicity of AML1-ETO is dependent on K43 acetylation by p300
- Loss of Id1 abrogates leukemia development in the mouse model of human leukemia
Selected Cancer-Related Publications
- Sun XJ, Wang Z, Wang L, Jiang Y, Kost N, Soong TD, Chen WY, Tang Z, Nakadai T, Elemento O, Fischle W, Melnick A, Patel DJ, Nimer SD, Roeder RG. A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis. Nature 500:93-7,2013 Read more »
- Vu LP, Perna F, Wang L, Voza F, Figueroa ME, Tempst P, Erdjument-Bromage H, Gao R, Chen S, Paietta E, Deblasio T, Melnick A, Liu Y, Zhao X, Nimer SD. PRMT4 Blocks Myeloid Differentiation by Assembling a Methyl-RUNX1-Dependent Repressor Complex. Cell Rep 5:1625-38,2013 Read more »
- Hatlen MA, Wang L, Nimer SD. AML1-ETO driven acute leukemia: insights into pathogenesis and potential therapeutic approaches. Front Med 6:248-62,2012 Read more »
- Liu F, Zhao X, Perna F, Wang L, Koppikar P, Abdel-Wahab O, Harr MW, Levine RL, Xu H, Tefferi A, Deblasio A, Hatlen M, Menendez S, Nimer SD. JAK2V617F-mediated phosphorylation of PRMT5 downregulates its methyltransferase activity and promotes myeloproliferation. Cancer Cell 19:283-94,2011 [JIF 26.925] Read more »
- Wang L, Gural A, Sun XJ, Zhao X, Perna F, Huang G, Hatlen MA, Vu L, Liu F, Xu H, Asai T, Xu H, Deblasio T, Menendez S, Voza F, Jiang Y, Cole PA, Zhang J, Melnick A, Roeder RG, Nimer SD. The leukemogenicity of AML1-ETO is dependent on site-specific lysine acetylation. Science 333:765-9,2011 [JIF 31.377] Read more »
Collaborating in the Multidisciplinary Research Program(s):