Behind the Lab Door: Shaoguang Li
On the pathway to a major break-through in treating polycythemia vera.
By Zhenya Senyak
Not many of us really want to know the details of the science behind drug discovery. The mind boggles at concepts like BCR-ABL and JAK2 mutations. Conceptually, the Philadelphia Chromosome is more remote than the Marianas Trench at the bottom of the Pacific Ocean.
But whether we understand the workings of science or not, the labs where it is practiced are where the real action is in our myeloproliferative world. Before a miracle drug hits the market, before clinical trials, there is only the bright blade of science interposed between us and our blood cancer.
Ever since an important signaling mutation, common to many with myeloproliferative neoplasms, was found five years ago, research has accelerated. With discovery of that JAK2 mutation (LINK), there has been an international explosion of research and publishing in the MPN arena, mostly focused on inhibiting the action of the JAK2 enzyme and its deadly effect on blood production.
One scientist is taking a different approach. And his big idea may soon advance us another giant step toward understanding and curing MPNs. And that cure is a common drug that might already be in our own medicine cabinet or the corner pharmacy.
This story starts in 沈阳 Shenyang, China, moves to its Sister City, Chicago, and is working its way to a conclusion in the Boston area.
What happened in Shenyang
Built on the plains of the Liao River, bordered by the forests of the Changai Mountains, the northeastern Chinese city of Shenyang has rarely been a peaceful place.
For half the 20th Century, Shenyang was at the center of war and occupation. The Japanese invaded in force to create the Manchuko State out of this portion of what was then Manchuria. After WWII, Shenyang became a civil war battleground as first Soviet troops
and then Chinese Nationalists occupied the city until driven out by the Chinese Communist forces in 1948. Today, this heavily industrialized Northeastern Chinese city — hot and humid in the summer, and very cold in winter — is home to over 8 million people. It is also home to the PRC’s first medical school, China Medical University (中国医科大学/中國醫科大學) It is in this city that Shaoguang Li grew up.
Shortly after graduating from China Medical School, Shaoguang Li, then a medical doctor, left to study in the United States. His primary interest was research with emphasis on leukemia. In the US, he studied at Tulane University in New Orleans earning his PhD degree for Cell and Molecular Biology. He went on to complete his post-doctoral degree at Harvard Medical School, obtained an appointment as Associate Professor at the University of Massachusetts and established his own lab. In the course of his work with Chronic Myeloid Leukemia (CML) he began to study a related blood disease, polycythemia vera (PV). This work produced a flash of insight.
He had a big idea he wanted to pursue. And to do it, he needed funding.
What happened in Chicago
For its 2010 grant program, the MPN Research Foundation sent out a Request for Proposals to individual researchers and medical research institutions. Sometimes these RFPs, as in the Foundation’s MF Concept Grants, are sharply focused. But in 2010, the Foundation cast a wide net trying to find both experienced and new investigators working on innovative research with high promise of productive results.
The competition was fierce, fueled both by MPN research stimulated by the JAK2 discoveries and the onset of the Great Recession of 2008. The prize: Nearly $1 million: Three $150,000/year two-year grants in Established Investigator Awards as well as $75,000 Awards to New Investigators. Only about 10% of all applicants would come away with anything.
Project coordinator Barbara Van Husen, president of the Foundation, would end up forwarding over 50 proposals to Dr. Andrew Schafer, Weill Cornell Medical School and head of the MPNRF Scientific Advisory Board. Dr. Schafer parceled out the proposals to teams of two reviewers each, to score each proposal individually.
After the scored proposals arrived back to the Foundation’s North Michigan Avenue HQ in Chicago, they were copied and shipped off to each of the 19 international scientific and academic advisors who would soon gather around the big conference table in Chicago to help determine what future direction MPN science might take.
Members of the preliminary review team presented their case, their reasons for assigning scores. During the ensuing discussions – sometimes lively – each adviser would assign his or her own score to a proposal. At the end, after tabulation and ranking of research proposals, there were further discussions. At stake: Funding science that may well alter the shape of basic MPN research for years.
Finally, the first awards are announced.
A $150,000 per year, two-year grant was awarded to Shaoguang Li.
The Lab at the University of Massachusetts
In Worcester, Massachusetts., on the outer ring of the Boston Metropolitan Area, is the Aaron Lazare Medical Research Building, the University of Massachusetts’ ten story curved glass high tech research facility. It is here that Shaoguang Li would take his grant to test his big idea.
The big idea
From his work with Leukemia Stem Cells (LSCs) in Chronic Myeloid Leukemia, Shaoguang knew that, among mouse populations, the ALox5 gene was necessary to induce CML. Remove the ALox5 and the LSCs were disrupted, essentially terminating the disease. He saw that there were essential similarities between CML and the myeloproliferative neoplasms, particularly polycythemia vera.
“Once he started looking at the MPNs and researching the JAK2 V617F mutation, it was obvious that it could not be the cause of MPNs – since MPNs existed in people who were negative for the mutation. There must be something downstream in the mutated JAK2 pathway, some recipient in the cell that’s actually critical to the onset of the disease.”
Part of that process seems clear: Phosphate groups act as on/off switches on proteins and when attached to certain cell receptors, JAK2 — a tyrosine kinase — has the ability to attach a phosphate group to itself (auto-phosphorylation). Mutant JAK2 becomes hopelessly auto-phosphorylated (ON), and endlessly signals hematopoietic stem cells to be more responsive to growth factors. In response to JAK2 signaling, the STAT gene is itself activated (phosphorylated) and translocates from the cell surface into the cell nucleus to trigger the DNA transcription of genes that results in translation into messages, cell differentiation, and in the case of MPNs, big trouble. And while pretty much everyone with PV has the JAK2 mutation, not even half those who are JAK2 positive have PV. What’s going on?
Since it appears that the mutated JAK2 enzyme might be signaling some cascade of events that do, in fact, cause PV, Shaoguang Li suspected the gene ALox5 was implicated in the pathway and would be an effective target gene to control PV. But where in the pathway would he find it?
Stopping you from driving to D.C.
“This is a brand new idea,” said Shaoguang Li. “Over the years, researchers have targeted the reason for disease, say the BCR-ABL function…We learned, however, that the BCR ABL or JAK2 or whatever, cannot induce disease without using key pathways in the cell.“
“So we began to identify the key pathways downstream …target the downstream pathway, alone or in combination with traditonal targeting of [mutations] like BCR-ABLE and JAK2. Let me give you an example. Where do you live?
“OK, let’s say you don’t fly. You drive from North Carolina to Washington D.C. So your car is critical for you to get from one place to another. However, what road are you going to take, this highway, that highway? For me to stop you from going from N.C. to D.C., I can make sure you can’t. I can break your car, give you a flat tire, no gas, do something on your car.
“But say I don’t know where your car is. I don’t know if you have people to protect your car… However, if I can find a way to block the key pathway to go from N.C. to D.C, like a key bridge to cross, and I block the bridge you cannot get to D.C. In order for you to achieve your objective, you have to have a car and your car has to have an available pathway.”
Seen in this light, — the Mapquest approach to genomic targeting — the Big Idea seems a little inevitable. But before Professor Li could blow up any pathway bridges he would have to first find the bridge that lies on the JAK2 polycythemia vera pathway. And to do that he needed mice.
How do you give a mouse PV?
Shaoguang’s plan was straightforward. He already had already seen that the Alox5 gene was essential to the development of a similar disease, CML, and he knew the mutant JAK2 protein activated several molecules that could be signaling the typical blood proliferation associated with PV, such as STAT5 and ERK.
What he didn’t know was whether Alox5 was upstream, between JAK2 and those molecules, or downstream, between the signaling molecules and the genes expressing proliferation. His lab started by using viruses to induce PV by introducing the expressed JAK mutation into the bone marrow cells of two types of mice. One is the so-called Wild Type (WT) or natural, and the other Alox5 knock- out or Alox-/- mice, mice totally without the Alox 5 gene. They would then transplant those cells into Wild Type mice.
Four months later, his lab separated proteins from the spleen cells of these mice and analyzed them, by detecting phosphorylation levels, to see which proteins had been activated. If Alox5 is upstream, these proteins would not be activated, if downstream they would. And if these signalling proteins had no relationship to Alox5 their state would be unchanged.
PV therapy – another part of the project
Whether active upstream or downstream, Professor Li was pretty sure from his earlier work on CML and PV, that the Alox5 gene was involved in the PV pathway. Is he right? It looks promising, but the work is still in process and he has one more year on his original grant to find out.
Shaoguan Li was principal author of a paper in Nature Genetics, in 2009, “Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia” in which he noted treatment of CML mice with an Alox5 inhibitors prolonged survival. There, he attributed the result to the targeting and inhibition of cancer stem cells. “In the absence of Alox5, BCR-ABL failed to induce chromic myeloid leukemia in mice.”
Under his MPNRF grant he now wanted to further test the mechanism and effectiveness of an Alox5 inhibitor in controlling PV over the long-term.
Zileuton, sold in your local pharmacy as Zyflo, a commonly used drug to prevent asthma attacks. It works because it’s a leukotriene inhibitor. Leukotrienes are those substances your body releases to close down parts of your airway when you breathe in substances to which you’re allergic.
What is Alox5 and why should we care anyhow?
Alox5 is a protein-coding gene, the name an abbreviation for arachidonate 5-lipoxygenase. The gene encodes a protein expressed in bone marrow cells and converts arachidonic acid to leukotrienes. These leukotrienes mediate many inflammatory and allergic conditions. Lipoxygenases are part of the LOX family we met earlier in the article on reversing fibrosis at Katya Ravid’s lab. For more information see http://www.genecards.org (ALOX5 Gene).
Is this work pioneering a new direction in PV and MPN research?
For 2000 years, from before Hippocrates on through today, a front line treatment for disease has been phlebotomy. Bleeding a patient has varied in intent – from purging bad blood and humors to balancing blood — and in technique, from blood sticks and leeches to hypodermic needles and venesection supplies. But whether accomplished by physicians, barbers or the blood letting leeches of the 19th Century, the therapeutic use of the technique today is fairly limited to the reduction of blood volumes in polycythemia or the iron overload of hemachromatosis.
(The barber pole is a holdover from those times, the red standing for blood, the white the tourniquet and the pole the blood stick.)
The development of drug therapies, most notably the use of hydroxyurea and an escalating choice of drugs aimed at the effects of the disease (interferons, primarily), has lessened the requirement for frequent phlebotomies. And, since nearly all PV patients carry the JAK2 genetic mutation, it’s anticipated that fairly soon one or more of the JAK inhibitors, now approved for myelofibrosis therapy, will be available to PV patients.
Advances in genomics, molecular biology and biotechnology permitting closer targeting of disease mechanisms will undoubtedly uncover new means to inhibit the ravages of PV.
And now, scientific research focused on the signalling pathway that leads from upstream mutation to ultimate proliferation promises a new direction, about as far from the barbershops and leeches as blood treatment can get.
© Zhenya Senyak and MPNforum.com, 2012. Unauthorized use and/or duplication of this material without express and written permission from this blog’s author and/or owner is strictly prohibited. Excerpts and links may be used, provided that full and clear credit is given to Zhenya Senyak and MPNforum.com with appropriate and specific direction to the original content.
Comments on: "On the pathway to beat polycythemia vera" (38)
Date of this comment: Jan 2023. I’m a 70+ yr old white male Vietnam combat veteran (US Army, 1969-1971, age then, 19-21 yrs old) w/substantial exposure, in 1969-1971, including ingestion of agent orange and I, now, have PV. Diagnosed Aug, 2021. I’ve had elevated hmt & hgb for over 40 yrs (generally, 50.1%, 50.3%, 50.4%…, but no higher). JAK2 positive(VA tested Aug 2021). Have received CBCs/phlebs (triggered by hmt over 45%) on 4 wk cycle(starting Sep 2021) for approx 4 mons. Hmt back to 47% w/each new cycle. Assigned diff hematologist who put me on 3 wk cycle (Feb 2022). Hmt% level dropping -1% each 3 wk cycle. After approx 3 mons became very short of breath, passed out 2 hrs after phleb while in parking lot. Absolutely, no prior negative events of any kind other than elevated bp sporadically. Very low iron levels. Hmt level at approx 43% (May 2022). Became short of breath & bedridden for 6 wks, unable to stand upright. Stopped phlebs, unable to drive myself to phleb ctr. In Sep 2022, confrontational mtg w/hematologist led to stopping phlebs. Now Jan 2023, hmt at 47%. No mtgs or phlebs til Dec 2022 and new hmt threshold of 50%. Next hematologist mtg scheduled Mar/Apr 2023. Decisions will be forthcoming from status at that time.
Additionally, I experienced migraine w/aura (w/o the pain), experienced only the visual effect of zig-zag neon lines overlaid on visual field starting as a single “pixel” at ctr of visual field slowly growing larger & larger til beyond edges of visual field and then being out of sight. Experienced this effect as many as twice a day and ofter 2-3 times a wk for 40 yrs. Never sought doctor evaluation for this effect. Approx 4 yrs ago on primary care physician recommendation started taking 81mg aspirin as cautionary, solely because of age pushing 70 yrs (note: no concerns for cancer at that time nor any thrombotic events had ever occured). Aura stopped completely. (For those unfamiliar with aura, they “appear” to be an optical affect but are not, they are a neurological affect).
Never smoked anything, no alcohol, no drugs of any kind ever. Only health issue was pneumonia at age 18 yrs for 10 days. 1-A health at induction to US Army at 19 yrs old. No health issues of any kind beyond elevated hmt & hgb for over 25 yrs (documented history), no documentation of hmt/hgb prior to 25 yrs ago.
I have recently been diagnosed with polycythemia vera. Any encouragement and info will be welcome
I was just diagnosed yesterday and as most it was very jaw dropping I have spent the majority of my life taking care of others in the medical field and now face the challenge of PV myself. I am scared to say the least as cancer has affected my family in so many ways and I refuse to give up and let this satin’s disease consume me. I may lose this battle one day but for now i will give 150% to try and be the one that beats it and I pray all of my fellow PV sufferers feel the same. I am also doing a lot of research on true CBD products and it to has many success stories… I will not let Satin gain any accomplishment from this diagnoses and I will not quit.. Prayers to you all and my hope is that we defeat this disease and make history!!!
Hi, Tiffany….Great attitude. Just by way of reassurance, in most cases, PV is a chronic MPN that can be managed through diligent monitoring and appropriate use of meds and venesection as — and if — required. The key is hooking up with an experience doc to partner on your journey. While it is possible for PV to progress to acute MPN phenotypes most patients enjoy long and normal lives without serious negative impacts on Quality of Life. Beyond all that we are well along in developing a full cure for PV through genetic advances and meantime there is interferon which has succeeded in producing full remission or minimal residual disease in several of your MPNforum neighbors. Keep in touch and keep safe over the holidays!
Zhen, the last study from Dr. Li that I can find is from 2017. I am thinking I read another report beyond the mice study was going to be published around the end of 2019 but I can’t find it. I often share Dr. Li’s work with other FB PV members and of course PV patients are interested in this concept of taking a simple readily available drug to change the downstream activation of the JAK2 mutation.
I didn’t wait for the final result of Dr. Li’s research and started taking Montelukast daily along with Pegasys. My results are very good with high over 75% AB falling to 25% in one year and then to 15% a year later. I suspect the 15% JAK2 mutation is not even actively PV now because of the Montelukast. My blood is now stable.
Do you know of any newer research than 2017 from Dr. Li?
Shaoguang li is a Professor at U Mass Medical Center. Tere’s a listing for him that includes an extensive bibliography including papers he’s published in the past few months.https://profiles.umassmed.edu/display/129949
Glad to hear of your results. Montelukast is a leukotriene inhibitor. If you’d like to share your story broadly with PV patients, how about writing an article for MPNforum on your experience? If you’re interested, jsut let me know… ourMPNforum@gmail.com.
Charlene, how were you able to get access to Montelukast? Did your hematologist agree to give you a prescription for it?
I found this article by searching polycythemia and traditional chinese medicine.
Not having any kind of medical knowledge, some of the text is hard to follow. My question is, has Zyflo been found to inhibit the ALox 5 gene?
Are there any clinical trials planned?
I’ve had PV for five years and have managed with phlebotomy and aspirin, so far. My doctor recommended Hydroxyurea. Hoping for something better. Possibly Ropeginterferon Alfa-2b if it is approved in U.S. later this year.
Any information would be appreciated.
For now, Donald, it makes sense to consider your Hu/INF options, both available and tested. A special report on the comparatives might be useful to you https://mpnforum.com/hu-int/. The Forum has also published many articles on this subject. Do check the ARCHIVES. Two reports you might find usefule are:
The Interferon Papers – Part III (INF and ET, PV, and MF …
https://mpnforum.com › the-interferon-papers-part-iii
An open letter on Interferon to US patients by Dr. Hans Hasselbalch
https://mpnforum.com › an-open-letter
This is very interesting news for pv sufferers. I would like more information on how to cope with this disease.
Hi, Shelby… If you go to the MPNforum home page (www.mpnforum.com) you’ll find links at the bottom to MPNclinics and the Archive of articles. The MPN clinics has specific answers to patient questions by some of the most skilled MPN specialists in the world. Check it out. The Archive has an index and graphics in the catalog to help… but it takes time to navigate. Just scroll through until you find an article dealing with PV or How I treat… or a specific med like interferon. The MPN Research Foundation is also a good resource to tap into. David Wallace has a newsletter PV Reporter that should also have items and links of interest to you.
My husband was recently diagnosed with PV, he’s 40. He is JAK2 negative. He has worked with asphalt for 20+ yrs, I’m wondering if the chemicals are why he has PV now and if he continues being exposed is it going to accelerate the PV process? I’m trying to learn as much as I can about this disorder. Thanks
He has reported complete data to MPD-RC for review and support in acquiring funding for the next phase
Exciting news! Thanks for your research. I had a question re: my PV. I know there’s no way to determine the precise causative agent, however, could my case have been caused by 4 abdominal ct scans within a 24 hour period? It was in the ER while being treated for kidney stones and an elevated white count.
How can we follow Professor Li’s work as it progresses from stage to stage?
Best bet for now, Brent is to stay tuned to MPNforum. We have reported on Dr. Shaoguang Li’s progress a few times, most notably in the feature story on Dr. Andrew Schafer in this issue of the Forum. https://mpnforum.com/schafer/ After our last conversation on his progress we were hopeful he would find a backer for clinical trial. We still are.
Attitude is 90% of winning the other ten percent has already won . Joey Malcolm
I usually hike once a week but missed three weeks in a row – I went Sunday it kicked my tail . It’s so important to keep moving and keep a work out regime . I don’t suffer from as bad fatique if I keep working out and hiking . I’ve registered on the few the proud the forgotten I’ve filed for VA compensation / disability .
It is amazing the research and dedication of these scientists and doctors . I have polycythemia Vera and I am jakv617 positive I was diagnosed about eighteen months ago afte a stroke . I received a letter from the marines about a month before my stroke stating they were researching disease cluster at camp Lejeune from toxic waters . Could my polychemia Vera have been caused by toxic water if I’m jakv617 positive ? Can someone let me know I’ve filed VA disability
Joseph, check out the facebook group that focuses on the Camp Lejeune contaminated water. Also check out tftptf.com (The Few The Proud The Forgotten) and do register as someone with a disease related to the water. They need to know what diseases people have who were exposed to help show a connection! There is an excellent documentary available at Netflix about the water and the work being done to show it has caused illnesses. I was diagnosed with PV also and drank the contaminated water for several years. There is also a closed Facebook group which you can join of people with PV who learn about the disease from each other.
Hi Joseph, I was stationed with 8th MTBn at French Creek, on Camp Lejeune from Jun 1984 to Dec 1985. I had a heart attack (blood clot) in March of 2011. Diagnosed with Polycythemia Vera in October 2017, which my hematology/oncology doctor said caused the heart attack in 2011. My email is AdvSec@aol.com, Sincerely, Brian
How do they test for the JAK2? My father has high red blood cell’s right now after doing a RBC Nuclear test and I am trying to get informed.
Thank you Zhenya for all that you do!
Very interesting and promising!
Fantastic news. Great report which does raise hopes for the future. All with PV and their families must hope that that this becomes a reality.
The New England Support group was fortunate enough to have him address our group last year. We were struck by the fact that he thanked us for coming and he said that it was exciting for him to meet people who he might someday be able to help. He is a modest and engaging person.
What an upper. I will certainly be interested in the outcome of this report, a cure could be around the corner.
Wonderful report. Thanks for sending it!
How soon before testing this inhibitor in MPN patients?
It’s important to remember that Professor Li is working with mouse populations in an experimental lab setting. If successful, the next step might be a dosing and toxicity clinical trial since the inhibitor likely exists. This is all pure conjecture because until his hypotheses are proven, we can only look over his shoulder and wait for the results. The possibilities are exciting and his concept of focusing on a gene in the pathway between the signaling mutated JAK2 and the DNA within the cell nucleus may well open new drug targets.
This is wonderful news and a great article. It’s so comforting to know that so many brilliant people are working on treatments and cures for these diseases.
Please tell Professor Li that those of us with PV are hanging in there waiting hopefully for progress in research on our disease. We thank him!
Great research with exciting new break threws in a very complicated illness! KUDO’S TO YOU!
Excellent report Zhen, this is exciting news!
Thanks for a look at the research, encouraging news to those of us with PV!!