Hwang, William Y.K.

Research Interests:

Haematopoietic Stem Cells
Multiple Myeloma

Haematopoietic Stem Cells

Umbilical cord blood (UCB) transplantation has evolved from being an experimental procedure, to a viable alternative for patients with no other options, and currently, to a treatment measure on par with other more established options. The robust proliferative potential, immunological naivete, and multipotency of UCB stem cells; coupled with the rapid availability of UCB, ability to tolerate mismatches and absence of donor risk allows UCB to meet the large, currently unmet, need for matched donor cells for transplantation. However, due to the limitation of cell numbers, adults have not benefited as much from this valuable resource.

Our Haematopoietic Stem Cell Laboratory seeks to study methods to improve the efficacy and utility of umbilical cord blood and other haematopoietic stem cells (HSC) in treatment of haematological and non-haematological malignancies. This is being accomplished through a concerted clinical and laboratory program to study, translate and develop new strategies for optimizing this valuable stem cell resource. As such, our research focuses on strategies to improve current methods for transplantation, homing and expansion of these HSC.

1) Improved strategies for haematopoietic stem cell transplantation (HSCT)

We currently running a number of clinical trials on newer strategies in HSCT. These include trials on pooled-unit cord blood transplantation, busulphan pharmacokinetic studies and GVHD. We are also running the SGH BMT Registry as well as the Singapore Cancer Syndicate Haematopoietic Transplant Coordinating Centre (HTCC) database, which will serve as a centralized database for HSCT in public hospitals in Singapore.

2) HSC homing

We are studying if intra-bone marrow cord blood injections improve homing and engraftment of cord blood stem cells, and also if this will have an impact on modulating immunotolerance between the cord blood graft and the patient. While the traditional route for HSC transplantation is intravenous, we found that intraosseus injection results in approximately 6-fold greater retention of HSC in the bone marrow (BM) and 2.5 to 5 fold fewer cells seeding onto peripheral organs like the recipient lung and heart. In addition, about 3-fold greater numbers of cells were found after IO injection in other BM cavities as well. This, together with data on the upregulation of fibronectin receptor CD49d after IO injection, but not CD18/ CD62L, suggests that IO injection not only delivers HSC directly to the appropriate microenvironment, but also modulates, grooms and educates HSC to express CAM resulting in better homing to other BM cavities even when the cells leak back into the blood stream.

3) Ex-vivo expansion of HSC

a) We have studied antibody-based approaches for ex-vivo cord blood expansion and have found that the addition of alemtuzumab, a clinical-grade anti-CD52 antibody, to actively deplete mature lymphocytes, granulocytes and monocytes during ex-vivo expansion of cord blood cells, results in enhancement of total cells, CD34+ cells, granulocyte-macrophage colony forming units (CFU-GM), long term culture initiating cells (LTCIC) and CD41+ megakaryocytic precursors.

b) Together with our collaborators, we have found that ex vivo expansion of cord blood cells on mesenchymal stem cell layers results in enhancement of HSC expansion without the need for prior CD34 / CD133 cell selection. We are currently determining the mechanism by which BMSC protect CB stem and progenitor cells. For example, what cell types can provide protection of CB stem and progenitor cells? Are adhesion molecules involved in the protection by BMSC? Do BMSC produce wnt, hoxB4 or notch factors? Will the blocking of growth factors or knock-down of adhesion molecules result in abrogation of the enhancement effect?

c) We are also assessing novel uses for the CB cells not used in the expansion process (e.g. CD133 negative), and whether they could be engineered for anti-tumor targeted cellular therapy.

d) To translate these strategies, we have also developed clinically validated protocols to assess if clinical-grade ex-vivo expansion of cord blood cells can overcome the barrier of low cell dose for patients requiring cord blood for transplantation.

Selected Publications:

Tang TF, Hou L, Chen M, Belle I, Mack S, Lancaster A, Ho GY, Hwang WY, Alsagoff F, Ng J, Hurley CK. HLA Haplotypes in Singapore: A Study of Mothers and Their Cord Blood Units. Human Immunology. 2007 May;68(5):430-8. Epub 2007 Feb 16.

Hwang WYK*, M Samuel, D Tan, LP Koh, W Lim, YC Linn. A Meta-Analysis of Unrelated Donor Umbilical Cord Blood Transplantation versus Unrelated Donor Bone Marrow Transplantation in Adult and Pediatric Patients. Biology of Blood and Marrow Transplantation. 2007 Apr;13(4):444-53. Epub 2007 Feb 15.

Koh LP, Chen CS, Tai BC, Hwang WYK, et al. Impact of Postgrafting Immunosuppressive Regimens on Nonrelapse Mortality and Survival after Nonmyeloablative Allogeneic Haematopoietic Stem Cell Transplant Using the Fludarabine and Low Dose Total Body Irradiation 2 Gy. Biology of Blood and Marrow Transplantation; 2007, Jul;13(7):790-805. Epub 2007 Apr 23.

Loh YSM, Hwang WY et al, Long-term follow-up of Asian patients younger than 46 years with acute myeloid leukemia in first complete remission: comparison of allogeneic versus autologous hematopoietic stem cell transplantation. Leuk Lymphoma. 2007 Jan;48(1):72-9.

Hwang WYK, Gullo CA et al. Decoupling Of Normal CD40 /Interleukin-4 Immunoglobulin Heavy Chain Switch Signal Leads to Genomic Instability in RPMI 8226 and SGH-MM5 Multiple Myeloma Cell Lines. Leukemia. 2006 Apr;20(4):715-23.

Loh SM, Ratnagopal P, Tan HC, Goh YT, Koh BC, Koh LP, Linn YC, *Hwang WY. Successful autologous hematopoietic stem cell transplantations for severe multiple sclerosis with fludarabine and cyclophosphamide conditioning. Int J Hematol. 2006 May;83(4):368-9.

Koh LP, Koh MB, Ng HY, Hwang WY, Goh YT, Linn YC, Ng HJ, Chuah CT, Tan KW, Loh YS, Tan DC, Tan PH, Tan PH. Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Severe Aplastic Anemia Following Nonmyeloablative Conditioning Using 200-cGy Total Body Irradiation and Fludarabine. Biol Blood Marrow Transplant. 2006 Aug;12(8):887-90.

Ting F.Tang, Lihua Hou, Bin Tu, William YK Hwang, Alan EJ Yeoh, Jennifer Ng, and Carolyn Katovich Hurley. Identification of Nine New HLA Class I Alleles in Volunteers from the Singapore Stem Cell Donor Registries. Tissue Antigens 2006 Dec;68(6):518-20.

Sun L, Hwang W, Aw SE. Biological Characteristics of Megakaryocytes: Specific Lineage Commitment and Associated Disorders. International Journal of Biochemistry and Cell Biology 2006 Volume 38(11):1821-1994.

Hwang WY, Foote J. Immunogenicity of engineered antibodies. Methods. 2005 May;36(1):3-10.

Hwang WY, Almagro JC, Buss TN, Tan P, Foote J. Use of human germline genes in a CDR homology-based approach to antibody humanization. Methods. 2005 May;36(1):35-42.

Hwang WYK et al. Randomized Trial Of Amifostine As A Cytoprotectant For Patients Receiving Myeloablative Therapy For Allogeneic Haematopoietic Stem Cell Transplantation. Bone Marrow Transplant. 2004 Jul;34(1):51-6.

PHC Tan, Hwang WYK*, YT Goh, PL Tan, LP Koh, CH Tan, TC Quah. Unrelated Peripheral Blood and Cord Blood Hematopoietic Stem Cell transplants for Thalassaemia Major. American Journal of Hematology 75:209–212 (2004).

Koh LP, Hwang WY, Tan CH, et al. Long term follow-up of Asian patients with chronic myeloid leukemia (CML) receiving allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical sibling –evaluation of risks and benefits. Ann Hematol (2004) 83:286–294.