QIMR Berghofer researchers have made a significant advance in unravelling the complex genetic events that can cause chronic blood cancers to progress to myelofibrosis or transform into an aggressive and deadly form of leukaemia.
People living with myeloproliferative neoplasms (MPNs), a group of rare chronic blood cancers, have no way of knowing if they are among the one third of patients who will progress to the life threatening disease.
The new research could hold the key to more accurately identifying high-risk MPN patients early and pave the way for new targeted treatments to prevent their disease from progressing.
MPNs are caused by genetic mutations in the blood-forming stem cells of the bone marrow. These mutations cause the stem cells to produce too many blood cells.
These abnormal cells can acquire additional mutations, causing MPNs to transform into severe diseases. These include myelofibrosis, which causes scarring in the bone marrow, and a type of blood cancer called acute myeloid leukaemia (post-MPN AML).
Leukaemia that forms from an MPN has a very poor prognosis. It’s usually treatment-resistant and fast-growing with a median survival time of six months or less.
The QIMR Berghofer team have developed a powerful new research method of single-cell analysis, called LOTR-Seq, to find the genetic pathways causing MPNs to transform into severe disease.
They uncovered distinct combinations of high-risk genetic mutations inside individual MPN cells that alter the behaviours of the cells and drive their progression to leukaemia.
Clinician-researcher Professor Steven Lane, who leads QIMR Berghofer’s Leukaemia Research Laboratory and is a clinical haematologist at the Royal Brisbane and Women’s Hospital (RBWH), said the research could lead to a shift in the way MPNs are managed.
“At the moment we can only treat disease symptoms. Our findings raise the possibility, for the first time, that we might be able to identify precursors of the genetic combinations that lead to leukaemia. That would give us the opportunity to act at that early stage to prevent the development of life-threatening disease,” said Professor Lane.
Study co-author Dr Jasmin Straube said there’s a need for greater understanding and awareness about MPNs.
“It is a significant mental burden for many MPN patients knowing that at any time they could progress to a severe disease with a dismal prognosis. It’s a massive driving factor for me to increase understanding so we can predict those at high risk and prevent their chronic disease progressing to leukaemia,” said Dr Straube.
The findings have been published in the journal, Blood Advances, and a step-by-step guide to using the LOTR-Seq method for the broader research community has been shared in STAR Protocols by Cell Press.
QIMR Berghofer Leukaemia Research Group co-laboratory head Dr Megan Bywater said one reason MPNs are challenging to study is that they each have many different cancer cell populations.
“Our goal is to understand the complex biology so we can improve outcomes for patients. It’s really exciting to have built this experimental method which is helping us solve this problem for the MPN community,” Dr Bywater said.
The research was led by Dr Jasmin Straube, Professor Steven Lane and Dr Megan Bywater from QIMR Berghofer's Leukaemia Research Laboratory
The team analysed more than 50,000 individual blood-forming stem cells from patients with chronic MPN and post-MPN leukaemia.
They searched for the most common genetic mutation that drives MPN, called JAK2V617, and identified nine additional mutations in six important genes (JAK2, IDH1/2, TP53, SRSF2, and U2AF1).
Each mutation was found to be associated with specific cellular behaviours that promote cancer, such as a cell becoming more aggressive, or multiplying rapidly, or remaining stuck in an immature stem-cell-like state.
The QIMR Berghofer researchers have now been awarded almost $3 million by the Federal Government’s Medical Research Future Fund (MRFF) Stem Cell Therapies Program to advance the discoveries. They will collaborate closely with MPN patient groups including MPN Alliance Australia.
The team plan to hold a clinical trial in the future to identify more high-risk combinations of genetic mutations in MPN patients.
They will also test a treatment, interferon alpha, that the lab has previously shown to target MPN stem cells. Participants would be monitored over two years to study how the drug works and see if it can eliminate the abnormal blood-forming stem cells.
The trial will combine their new LOTR-Seq method with cutting edge spatial tissue analysis technologies that have been part funded by the Australian Cancer Research Foundation Centre of Optimised Cancer Therapy (ACRF-COCT).
Dr Straube said: “Spatial technology allows us to map the location and behaviour of the disease-driving stem cells hiding in the bone marrow and see how they’re interacting with neighbouring cells. We know these stem cells don’t act in isolation, so potentially we can target these interactions as well as the cancer-causing stem cells to really drive them out of the bone marrow.”
Supporters of the research include the National Health and Medical Research Council (NHMRC), Cancer Council Queensland, the Haematology Society of Australia and New Zealand (HSANZ), Leukemia Foundation, Australian Cancer Research Foundation (ACRF), and the German Academic Exchange Service (DAAD).