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Shaoguang Li MD, PhD

TitleProfessor
InstitutionUMass Chan Medical School
DepartmentMedicine
AddressUMass Chan Medical School
364 Plantation Street LRB
Worcester MA 01605
Phone508-856-1691
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    Other Positions
    InstitutionT.H. Chan School of Medicine
    DepartmentMedicine
    DivisionHematology Oncology

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentCancer Biology

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentInterdisciplinary Graduate Program

    InstitutionUMass Chan Programs, Centers and Institutes
    DepartmentCancer Biology


    Collapse Biography 
    Collapse education and training
    China Medical University, Taichung City, , ChinaMD
    Tulane University, New Orleans, LA, United StatesPHDCell & Molecular Biology

    Collapse Overview 
    Collapse overview

    Current Research

    Molecular Basis and Stem Cell Biology of Human Philadelphia Chromosome-positive Leukemias

    The human Philadelphia chromosome arises from a translocation between chromosomes 9 and 22, and results in formation of the chimeric and constitutively activated BCR-ABL tyrosine kinase. Philadelphia chromosome-positive (Ph+) leukemias induced by the BCR-ABL oncogene include chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL). CML often initiates in a chronic phase and eventually progresses to a terminal blastic phase, in which either acute myeloid or acute B-lymphoid leukemia develops. Some Ph+ leukemia patients, however, have B-ALL as their first clinical appearance. It is generally believed that shutting down the kinase activity of BCR-ABL will completely inhibit its functions, leading to inactivation of its downstream signaling pathways. Therefore, current therapeutic efforts have focused on targeting BCR-ABL kinase activity using kinase inhibitors.
    The BCR-ABL tyrosine kinase inhibitor imatinib mesylate (Gleevec) is the standard of care for Ph+ leukemia. Imatinib induces a complete hematologic response in chronic phase CML patients. However, imatinib does not completely eliminate BCR-ABL-expressing leukemia cells, and some patients present with drug resistance. Imatinib prolongs survival of mice with BCR-ABL-induced CML, but does not cure the disease. Other BCR-ABL kinase inhibitors, such as dasatinib, nilotinib, etc., have been shown to inhibit almost all imatinib-resistant BCR-ABL mutants; the exception is the T315I mutant, which is present in 15-20% of imatinib-resistant patients. Dasatinib is also a potent inhibitor of SRC family kinases, but the role of the anti-SRC activity of this compound in Ph+ leukemia therapy is unclear. In general, these BCR-ABL kinase inhibitors are less effective in treating CML blastic phase patients and patients with Ph+ B-ALL. Recently, ponatinib, which has an activity against the BCR-ABLT315I, has been approved by FDA for treating CML patients with BCR-ABL mutations including the T315I, and future clinical trials will show the effectiveness of this new BCR-ABL kinase inhibitor. Although BCR-ABL kinase inhibitors are effective in controlling CML, it is generally believed that they will not cure the disease because a small group of BCR-ABL-expressing leukemia stem cells (LSCs) are insensitive to inhibition of BCR-ABL kinase activity. Now it becomes clear that LSCs are basically resistant to inhibition by BCR-ABL kinase inhibitors. Therefore, we decided to study molecular mechanisms for survival and self-renewal of LSCs in CML.

    It is feasible to specifically target LSCs
    To identify CML stem cells, we tested whether BCR-ABL-expressing hematopoietic stem cells (HSCs) function as the stem cells. To do so, we isolated bone marrow cells from CML mice, and sorted the BCR-ABL-expressing HSCs (GFP+Lin- Sca-1+c-Kit+) by FACS. The sorted cells were then transferred into recipient mice, and the mice developed and died of CML, indicating that BCR-ABL expressing HSCs function as CML stem cells. With our method of isolating LSCs in CML mice, we decided to further understand the biology of LSCs and to identify selective and effective target genes that play key roles in survival and self-renewal of these LSCs. Based on our DNA microarray data and genetic validation of candidate genes in our leukemia mouse models, we have identified a group of genes that are essential for the functions of LSCs, shedding light on developing an anti-stem cell therapy for CML. For example, we have shown that the survival and self-renewal of LSCs but not normal hematopoietic stem cells require the arachidonate 5-lipoxygenase (5-LO) gene (Alox5) and that Alox5 is essential for CML development (Chen et al. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nature Genetics 41:783-792, 2009). We have also identified several other LSC-specific genes such as Msr1 (Chen et al. A tumor suppressor function of the Msr1 gene in leukemia stem cells of chronic myeloid leukemia. Blood 118:390-400, 2011), Blk (Zhang et al. The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells. Nature Genetics 44:861-871, 2012), etc.

    BCR-ABL activates some pathways in a kinas-independent manner
    If BCR-ABL kinase inhibitors efficiently inhibit BCR-ABL kinase activity, we wonder why these inhibitors would not shut down all pathways activated by BCR-ABL, as mentioned above. Our hypothesis is that BCR-ABL activates its downstream pathways through both kinase activity-dependent and independent mechanisms. In fact, we have identified a group of genes whose expression is alter by BCR-ABL, but BCR-ABL kinase inhibitors cannot restore their expression; examples of these genes include Alox5, Msr1, Blk, etc. Regulation of expression of these BCR-ABL kinase activity-independent genes provides a novel mechanism explaining why LSCs are resistant to BCR-ABL kinase inhibitors and why these inhibitors are unlikely to cure CML. We plan to further explore this BCR-ABL kinase activity-independent mechanism in LSCs of CML. Our effort will help to develop novel anti-stem cell therapeutic strategies for curing CML, and knowledge learned from studying LSCs of CML will help to understand the biology of cancer stem cells in other malignant diseases.



    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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    PMC Citations indicate the number of times the publication was cited by articles in PubMed Central, and the Altmetric score represents citations in news articles and social media. (Note that publications are often cited in additional ways that are not shown here.) Fields are based on how the National Library of Medicine (NLM) classifies the publication's journal and might not represent the specific topic of the publication. Translation tags are based on the publication type and the MeSH terms NLM assigns to the publication. Some publications (especially newer ones and publications not in PubMed) might not yet be assigned Field or Translation tags.) Click a Field or Translation tag to filter the publications.
    1. Li D, Li S. An artificial intelligence deep learning platform achieves high diagnostic accuracy for Covid-19 pneumonia by reading chest X-ray images. iScience. 2022 Apr 15; 25(4):104031. PMID: 35280932.
      Citations:    
    2. Li D, Bledsoe JR, Zeng Y, Liu W, Hu Y, Bi K, Liang A, Li S. A deep learning diagnostic platform for diffuse large B-cell lymphoma with high accuracy across multiple hospitals. Nat Commun. 2020 11 26; 11(1):6004. PMID: 33244018.
      Citations: 9     Fields:    Translation:Humans
    3. Ma L, Pak ML, Ou J, Yu J, St Louis P, Shan Y, Hutchinson L, Li S, Brehm MA, Zhu LJ, Green MR. Prosurvival kinase PIM2 is a therapeutic target for eradication of chronic myeloid leukemia stem cells. Proc Natl Acad Sci U S A. 2019 05 21; 116(21):10482-10487. PMID: 31068472.
      Citations: 5     Fields:    Translation:HumansAnimalsCells
    4. Shan Y, DeSouza N, Qiu Q, Li S. Leukemia Stem Cells in Chronic Myeloid Leukemia. Adv Exp Med Biol. 2019; 1143:191-215. PMID: 31338821.
      Citations: 2     Fields:    Translation:HumansAnimalsCells
    5. Chen Y, Shan Y, Lu M, DeSouza N, Guo Z, Hoffman R, Liang A, Li S. Alox5 Blockade Eradicates JAK2V617F-Induced Polycythemia Vera in Mice. Cancer Res. 2017 01 01; 77(1):164-174. PMID: 27784744.
      Citations: 3     Fields:    Translation:HumansAnimals
    6. Li S. Fighting fat in AML. Blood. 2016 10 13; 128(15):1910-1911. PMID: 27737846.
      Citations:    Fields:    Translation:Humans
    7. Ma L, Shan Y, Bai R, Xue L, Eide CA, Ou J, Zhu LJ, Hutchinson L, Cerny J, Khoury HJ, Sheng Z, Druker BJ, Li S, Green MR. A therapeutically targetable mechanism of BCR-ABL-independent imatinib resistance in chronic myeloid leukemia. Sci Transl Med. 2014 Sep 03; 6(252):252ra121. PMID: 25186176.
      Citations: 58     Fields:    Translation:HumansAnimalsCells
    8. Chen Y, Li S. Molecular signatures of chronic myeloid leukemia stem cells. Biomark Res. 2013 Jun 06; 1(1):21. PMID: 24252550.
      Citations:    
    9. Zhang H, Li S. Molecular mechanisms for survival regulation of chronic myeloid leukemia stem cells. Protein Cell. 2013 Mar; 4(3):186-96. PMID: 23483480.
      Citations: 16     Fields:    Translation:HumansAnimalsCells
    10. Yang ZF, Zhang H, Ma L, Peng C, Chen Y, Wang J, Green MR, Li S, Rosmarin AG. GABP transcription factor is required for development of chronic myelogenous leukemia via its control of PRKD2. Proc Natl Acad Sci U S A. 2013 Feb 05; 110(6):2312-7. PMID: 23345428.
      Citations: 15     Fields:    Translation:AnimalsCells
    11. Ho N, Li A, Li S, Zhang H. Heat shock protein 90 and role of its chemical inhibitors in treatment of hematologic malignancies. Pharmaceuticals (Basel). 2012 Jul 25; 5(8):779-801. PMID: 24280675.
      Citations:    
    12. Zhang H, Peng C, Hu Y, Li H, Sheng Z, Chen Y, Sullivan C, Cerny J, Hutchinson L, Higgins A, Miron P, Zhang X, Brehm MA, Li D, Green MR, Li S. The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells. Nat Genet. 2012 Jul 15; 44(8):861-71. PMID: 22797726.
      Citations: 33     Fields:    Translation:HumansAnimalsCells
    13. Peng C, Chen Y, Shan Y, Zhang H, Guo Z, Li D, Li S. LSK derived LSK- cells have a high apoptotic rate related to survival regulation of hematopoietic and leukemic stem cells. PLoS One. 2012; 7(6):e38614. PMID: 22675576.
      Citations: 9     Fields:    Translation:AnimalsCells
    14. Zhang H, Li H, Ho N, Li D, Li S. Scd1 plays a tumor-suppressive role in survival of leukemia stem cells and the development of chronic myeloid leukemia. Mol Cell Biol. 2012 May; 32(10):1776-87. PMID: 22431519.
      Citations: 19     Fields:    Translation:AnimalsCells
    15. Zhang H, Li H, Xi HS, Li S. HIF1? is required for survival maintenance of chronic myeloid leukemia stem cells. Blood. 2012 Mar 15; 119(11):2595-607. PMID: 22275380.
      Citations: 97     Fields:    Translation:AnimalsCells
    16. Chen Y, Sullivan C, Peng C, Shan Y, Hu Y, Li D, Li S. A tumor suppressor function of the Msr1 gene in leukemia stem cells of chronic myeloid leukemia. Blood. 2011 Jul 14; 118(2):390-400. PMID: 21596859.
      Citations: 14     Fields:    Translation:HumansAnimalsCells
    17. Peng C, Chen Y, Li D, Li S. Role of Pten in leukemia stem cells. Oncotarget. 2010 Jun; 1(2):156-60. PMID: 21297225.
      Citations: 20     Fields:    Translation:HumansAnimalsCells
    18. Chen Y, Peng C, Li D, Li S. Molecular and cellular bases of chronic myeloid leukemia. Protein Cell. 2010 Feb; 1(2):124-32. PMID: 21203982.
      Citations: 21     Fields:    Translation:HumansAnimalsCells
    19. Chen Y, Peng C, Sullivan C, Li D, Li S. Novel therapeutic agents against cancer stem cells of chronic myeloid leukemia. Anticancer Agents Med Chem. 2010 Feb; 10(2):111-5. PMID: 20184539.
      Citations: 8     Fields:    Translation:HumansAnimalsCells
    20. Peng C, Li S. CML mouse model in translational research. Methods Mol Biol. 2010; 602:253-66. PMID: 20012403.
      Citations: 8     Fields:    Translation:HumansAnimalsCells
    21. Peng C, Chen Y, Yang Z, Zhang H, Osterby L, Rosmarin AG, Li S. PTEN is a tumor suppressor in CML stem cells and BCR-ABL-induced leukemias in mice. Blood. 2010 Jan 21; 115(3):626-35. PMID: 19965668.
      Citations: 60     Fields:    Translation:HumansAnimalsCells
    22. Chen Y, Li D, Li S. The Alox5 gene is a novel therapeutic target in cancer stem cells of chronic myeloid leukemia. Cell Cycle. 2009 Nov 01; 8(21):3488-92. PMID: 19823023.
      Citations: 28     Fields:    Translation:HumansAnimalsCells
    23. Chen Y, Hu Y, Zhang H, Peng C, Li S. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nat Genet. 2009 Jul; 41(7):783-92. PMID: 19503090.
      Citations: 117     Fields:    Translation:AnimalsCells
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