How the MPNs are classified is set to change with eight new classifications based on the underlying mechanisms that drive the mutations, according to international MPN expert, Professor Tony Green.

His Green lab at Cambridge University has been pivotal in identifying the new genetic groups that are expected to replace the “conventional way” of categorising people with MPN used “for 100 years or more”.

Early in his career, Professor Green found haematology “fascinating” because it allowed him to do research that he couldn’t have done in other areas of medicine.

“You get blood cancer in the blood and in the bone marrow, where the action is. You can’t do that [research] in the brain very easily… patients tend to complain!” he said.

Although a consultant haematologist and “clinician by trade”, Prof. Green has spent 80% of his 30-year career in research leadership roles.

He heads his own research group, is the Head of the University of Cambridge Department of Haematology, Professor of Haemato-Oncology at the University of Cambridge, and Director of the Cambridge Stem Cell Institute. He also is a recent president of the European Hematology Association.

Research at the Green laboratory at Cambridge

The driver for most scientists, he says, is understanding how things work.

“Once you understand how things work, or how things have gone wrong in the case of a blood cancer, you can use that knowledge to manage patients with those diseases better. Whether it’s to diagnose them better, treat them better, or give them better information about their prognosis,” said Prof. Green whose lab works in three broad areas.

One uses information “we now have” to make a difference in the clinic, and the second is “more biological” – trying to understand how mutations cause the changes they do.

“How does a mutation in a particular gene, like JAK2, result in the sort of diseases that it does? How does it cause the stem cells to go wrong or the red blood cell progenitors to increase?” said Prof. Green.

“There’s a lot we don’t understand about the mechanisms there.

“Quite often, when you study something abnormal, you learn stuff about the normal, and vice versa,” said Prof. Green about the third area – the unexpected insights that are stumbled across, “such as discovering how the normal regulation of blood cell formation works while trying to understand how the mutations work and the pathways they are part of”.

Referring to the clinical impact of his research, Prof. Green highlighted two messages he thought MPN News readers might want to know from a paper titled Classification and Personalized Prognosis in Myeloproliferative Neoplasms, published in the New England Journal, in October 2018.

A new classification system for MPNs

The first was a new way of classifying the MPNs.

“Until now, we have used the old-fashioned terms to describe patients. We put them into categories – polycythaemia vera (ET), essential thrombocythaemia (ET), myelofibrosis (MF)… based on describing what we see in the patient… too many red cells, too many platelets. It’s a phenotype*-based classification,” Prof. Green explained.

“There are lots of different causes of too many red blood cells and lots of different causes of too many platelets.

“What you really want is a classification based on the underlying mechanisms. The mechanisms that drive these diseases are all the different mutations.

“We’ve looked at 2000 patients with many, many different mutations,” he said.

Based on genome classification, eight separate genomic groups were identified according to the mutations each patient had and covering the gamut of MPNs. And each of those eight groups included some people with what would have been called PV, some with what would have been called ET, and some with what would have been called MF.

“Those eight groups are defined by the real biological causes of these diseases,” said Prof. Green.

“I think this is going to be a much more robust and objective way of categorising patients, which will make it easier when it comes to doing clinical trials, which will have patients stratified into those eight groups rather than the rather subjective names that we give these diseases at the moment.”

The second aspect of the paper was the result of using the “very large database” of 2000 people and “all our clinical and molecular data to generate a way of giving an individual patient a personal prognosis, which is something we couldn’t do”.

“Because what tends to happen is… we put people into groups. We say you are low-risk or high-risk. But low-risk has a whole mixture of people in it and high-risk has a whole mixture of people in it. So, we didn’t know where an individual person fitted in.

“Now we have been able to do that,” said Prof. Green.

“Comparing data from a patient in the clinic to the 2000-patient data bank, we can say with some sort of confidence, ‘well Mrs Jones, you have approximately a 20% chance of developing AML five years from now’.”

Prof. Green expects patients would have polygenic tests** and those results would be combined with their age, gender, laboratory data, blood counts, etc.

“Put that all together and you can give somebody a much more personal idea of what their outlook might be,” he said.

The question now, Prof. Green said, was how this new form of classification would be implemented by individual clinicians and applied in clinical trials.

“It will take a little time for change to occur, and it will be interesting to see how quickly this is picked up and how rapidly it is used,” he said.

“I suspect it will be used more in clinical trials to begin with because you can stratify your patients going into a clinical trial into these eight groups.”

He also expects, initially, that this genomic approach will be compared with the conventional way of categorising patients in a controlled, clinical setting.

Prof. Green said applying the genomic classifications in the clinic would mean genomic sequencing of all MPN patients.

“There are quite a few steps that need to be put in place before this can be set up and run routinely in the clinic.”

World-leading MPN research

In 1995, the Green lab set up “the largest randomised clinical trial ever in any MPN” – the PT1 study.

“The group in Cambridge is unusual. We span everything from large clinical trials through to identifying the mutations, through to understanding what the mutations do,” said Prof. Green.

“Our main strength is trying to understand the disease, and the diagnosis and prognosis stage, which I think is really essential.

“I don’t work at the bench anymore,” said Prof. Green, who has up to 15 researchers in his lab – a mixture of a PhD students, technicians and post-docs.

“I try to sit down with them as a group once a week, and individually, which is variable but ideally is once a week.

“My role is to provide a bit of strategic direction and help keep the focus in the right place, rather than going off on tangents.”

He said some people on his team were good at making mouse models. One post-doc was “absolutely superb” at all the protein signaling-type approaches and transcription regulation – the molecular biology, and others have expertise in methylation changes – the cell biology of what’s going on.

“To understand a disease properly, you really need people to understand the cell biology,” said Prof. Green.

“Sometimes you get taken into apoptosis, or cell death. Sometimes you get taken down into mechanisms of receptor signaling, and other times you are down in the nucleus asking questions about transcription and chromatin.

“And, depending on where our results lead us and the sort of question we are trying to answer, the group evolves.”

What a difference 20 years makes

Prof. Green said the field “had moved fantastically over the last 20 years”.

“If you look across the blood cancers, the number of advances that have made an enormous difference to patients has been very exciting.

“One can point to several diseases where, 20 years ago, a patient with a particular cancer, would almost invariably be dead within five years.

“Now, they are alive and well 20 years later. They may not be completely cured, but what we have achieved has made an enormous difference.”

A word of advice

Prof. Green offered people with MPN some advice.

“This is so easy to say and very difficult to do… those with a very positive approach to their disease, who are just getting on with it and letting it interfere with their lives as little as possible – that has got to be the way to go.

“There is a lot of life to live out there, family to spend time with, all that stuff. Don’t let it [an MPN] get in the way. Easy to say, difficult to do.

“MPN has a relatively slow and long trajectory. They do progress; ET and PV slowly but surely over many years,” he said.

“If you follow somebody for sufficiently long, many will develop either MF, or the unlucky ones will develop acute myeloid leukaemia. But it is such a long trajectory that a large proportion of them will die from something else.

“Most come with chronic phase PV, or ET, and one of the things I absolutely say up front is… if you have got to have a disease, this is the one to have, because most people with chronic phase disease will die of something else, not their disease. They will die with their disease, but not from it.

“I try and give them the information we have about what their personal outlook might be. It’s too easy for people to think they have got a blood cancer and they are going to die, it’s not like that for MPNs,” said Prof. Green.

Professor Green’s holy grail

Prof. Green has two holy grails which he would like to see achieved during his career, and the first is “a targeted therapy that works”.

“The JAK2 inhibitors are not targeted to the mutation,” he said.

“We need a better way of targeting. What we want is a JAK2 inhibitor that only hits the mutant. That is a long way off, but it would be nice.

“And, then, in terms of the consequences, I’d like to really understand in humans how this mutation [JAK2] arises. We are starting to get this information. We can now do lineage tracing in man, so we can look at a patient and we can say ‘your JAK2 mutation arose when you were five’.

“But what we don’t know is how that mutation changed your stem cells back then. So, getting a better understanding of what is going on in the patient looking back is the second holy grail.”

* The physical appearance or biochemical characteristic of an organism as a result of the interaction of its genotype and the environment.

** A polygenic score, also called a polygenic risk score, genetic risk score, or genome-wide score, is a number based on variation in multiple genetic loci and their associated weights.