We offer this tribute to Dr. Guang Yang, who, after 13 years of service to the Bing Center (20 years at Dana-Farber), will be moving on to continue his career in the bio-pharmaceutical industry. Please join us in thanking him for his outstanding contributions in advancing our knowledge for the benefit of the WM community worldwide.

Dr. Guang Yang is a Senior Scientist at Dana-Farber Cancer Institute (DFCI). He joined DFCI in 2001 following graduation from the Cancer Institute/Hospital of Chinese Academy of Medical Sciences (CAMS) at Peking Union Medical College (PUMC) in Beijing, China. As a Research Associate in Dr. Benz's lab, he was focused on gene expression regulation studies and published several peer-reviewed papers in Blood, Molecular Cells, etc. In 2008, he joined the Bing Center for Waldenstrom's Macroglobulinemia (WM) as a Research Fellow and then promoted to an Instructor in Medicine at Harvard Medical School. After the milestone discovery of MYD88-L265P somatic mutation in WM patients, his research has focused on mutated MYD88 signaling in B-cell malignancies. It demonstrated that MYD88-L265P triggers pro-survival NF-κB signaling in primary WM patient tumor cells (Treon et al. NEJM 2012.). This finding had a tremendous impact on the WM field by identifying MYD88-directed signaling as a novel therapeutic target for WM. He was the first to report Bruton Tyrosine Kinase (BTK) and Hematopoietic Cell Kinase (HCK) are downstream targets of mutated MYD88 signaling. These discoveries demonstrated that the pro-survival NF-kB signaling is driven by both BTK and IRAKs (Yang et al. Blood 2013), and HCK triggers pro-survival BTK, PI3K/AKT, and MAPK/ERK signaling (Yang et al. Blood 2016). The discovery of BTK as a downstream target of mutated MYD88 provided the scientific basis for the ibrutinib clinical trial (NCT01614821) in WM and subsequent fast-track, breakthrough designation, and accelerated approval by the U.S. FDA.

The finding of HCK as a downstream mediator of mutated MYD88 survival signaling prompted efforts to develop HCK inhibitors to treat MYD88 mutated malignancies. HCK inhibitors/degraders with potent activities against MYD88 mutated B-cell lymphoma cells have been developed in collaboration with Nathanael Gray's group at Harvard Medical School. Our combined efforts have also identified several novel compounds that target previously known and unknown kinases in mutated MYD88 signaling. The lead HCK inhibitor is under intensive preclinical investigation and showed promising results in PK/PD, in vitro cellular, ex vivo primary patient-derived tumor cells, and in vivo efficacy studies, as well as DMPK studies. Most importantly, the lead HCK inhibitor showed promising application to overcome Ibrutinib resistance caused by BTKCys481 mutations in vitro and a xenografted mouse model. And now, the lead HCK inhibitor is in IND-enabled studies. Three U.S. patents have been approved on related discoveries, and several more patents are filed and waiting for approval.

Dr. Yang also led the ibrutinib resistance mechanism study efforts and identified that subclonal BTKCys481 mutations drive ERK1/2 persistent activation and IL-6/IL-10 production that are responsible for the acquired ibrutinib resistance in WM patients. The subclonal BTKCys481 mutations even protect BTK wild-type tumor cells from ibrutinib-induced cell death through a paracrine mechanism (Chen et al. Blood 2018). This work was the first to provide evidence for the tumor cells clonal cooperativity in mediating ibrutinib resistance, and led to clinical trials using Dasatinib (NCT04115059) to treat BTKCys481 mutated ibrutinib resistant WM patients.

In addition to MYD88 signaling, Dr. Yang's team also identified the overexpression of Bcl-2 in WM and reported the synergistic effect by the combination of Bcl-2 inhibitor, ABT-199 with BTK inhibitor, Ibrutinib (Cao et al. BJH 2015). This work led to a clinical trial in WM (NCT02677324; NCT04273139).

Dr. Yang is also a co-investigator in several projects supported by the NIH SPORE grant, LLS translational program, and IWMF legacy grant to develop targeted therapeutics for MYD88 mutated diseases. Their candidates that include novel HCK inhibitors/degraders, IRAK1 inhibitors, are under intensive preclinical investigations.

When asked what he most enjoyed about working at the Bing Center, Dr. Yang answered: "What I most enjoyed about working at the Bing Center was to work with the world leading doctors and scientists to make breakthrough scientific discoveries and work like a family where everyone is caring about each other."

Dr. Yang's 13 years of research at the Bing Center into the causes of Waldenstrom's Macroglobulinemia have furthered our understanding of this rare hematological malignancy. His efforts have contributed to the development of novel treatments, extending the quality of life of WM patients, and bringing us closer to a cure. We wish him all the best as he moves on to the next phase of his career.

A personal note from Lian Xu, fellow researcher at the Bing Center:

I first met Guang Yang in June, 2008, when I was doing an experiment in my lab. A young man with thick eyebrows and big eyes smiled and asked if this was Dr. Treon's lab. In a few weeks, Guang was a member of our team. He started at the lab as a research fellow and has worked his way up to become one of the key members of WM's research in Steve’s laboratory over the years.

Guang is mainly responsible for the MyD88 pathway functional study as well as drug development for WM. He patiently mentors and encourages the young students and researchers in the group. He is extremely serious, careful and responsible for his work. He is always full of enthusiasm and research spirit for his scientific research projects and is very friendly to colleagues. If we encounter problems in the experiment, he is always willing to provide good suggestions and help. There are also many hobbies, such as playing soccer, cooking and traveling. Guang’s cooking skills are also very good. We once went to Guang’s family party. Guang made roast mutton skewers. The delicious taste of the memory is still new.

The Bing Center for WM is a place full of hope and energy, where everyone is passionate about their work, studying science, helping each other, accepting and encouraging their colleagues. Although I also left Steve's Lab due to family reasons, as a researcher who has worked in the Bing Center for 16 years, I have deep feelings for Steve's Lab, and my heart will always be tied to the WM community. I believe that Guang shares the same feelings with me. Now Guang is about to leave the WM team and work in a bio-pharmaceutical company. I sincerely wish Guang all the best in his new job and continued success in the future.

Click to view a short video slideshow in honor of Dr. Guang Yang