Adult leukaemia can be caused by gene implicated in breast cancer and obesity

January 16, 2018 by Samantha Le Sommer, The Conversation
AML under the microscope. Credit: Medtech THAI STUDIO LAB 249

When people think of leukaemia, they usually think of blood cancers that affect children. These mostly come under the category of acute lymphoblastic leukaemia – or ALL – and are different to the group of blood cancers which predominantly affect adults over the age of 60, known as acute myeloid leukaemia (AML).

AML accounts for about 90% of all leukaemias in adults, though it affects some children too. With some 3,000 new cases each year in the UK alone, it is tougher to treat than ALL.

Where advances in ALL treatment have raised survival rates to around 90% over the past several decades, the rates for surviving the less well researched AML are more like 65%. Older adults respond least well to treatment, with only 5% of over-65s surviving more than five years.

I am therefore pleased to report a promising discovery. Work in which I have been involved has shown that a particular gene can play a critical role in the development of the disease. This could be the precursor to a breakthrough that could be life-saving for patients.

Cells and treatments

Your bone marrow contains stem which divide and differentiate into red blood cells and the main groups of , neutrophils and lymphocytes. Normally this happens in a very controlled manner, ensuring you have all the needed to carry oxygen around your body, and all the white blood cells needed to fight off infections.

In AML too many immature myeloid cells are produced too quickly by the bone marrow. They are mutant cells which don't mature, meaning they fail to defend against infection.

For this reason, early signs of AML include flu-like symptoms, aches and pains in the joints, and rapid weight loss. As the abnormal cells build up inside the bone marrow or the blood they grow and divide aggressively. Left untreated, AML patients can have only weeks to live.

Patients are normally treated by two stages of chemotherapy over a few months: an induction phase which reduces the number of cancer cells to undetectable levels, then a consolidation phase to kill any cancerous cells hiding in the body. Patients often also receive a , effectively giving them a new immune system.

Treating AML is complicated by patients generally being older, since they tolerate the intensive chemotherapy less well. In many cases, they receive some treatment and end up only living a few months. Better understanding the mutations to develop more targeted and less harsh treatments looks like the key to improving survival.

Bone marrow transplant. Credit: El-Roi

Step forward, PTPN1

A number of mutations are associated with AML, and often occur in combinations. It's these mixtures of mutations that are thought to cause the complex subtypes of cancers within the AML group. One common mutation is called Del20q. It involves the deletion of part of chromosome 20, one of the 23 pairs of chromosomes most humans have in all their cells.

It has long been suspected that genes on this part of the chromosome may function, either individually or together, to suppress cancer. Until recently, however, researchers have found it hard to say which genes are responsible.

One candidate is known as PTPN1, or protein tyrosine phosphatase, non-receptor type 1. First discovered in the late 1980s and linked to metabolic function, it is more famously known for its roles in breast cancer and type 2 diabetes. Its location on chromosome 20 has long made specialists suspect it could also be involved in AML.

It was shown recently that when you switch off the equivalent gene in mice, it leads to what are known as myeloproliferative neoplasm, which is the wider family of of which AML is a member. In our new study, we have taken this a step forward: we have shown that if you delete this gene in older mice, it specifically gives rise to AML – and in a similar way to how the disease develops in older humans.

The previous study showed that PTPN1 is deleted from chromosome 20 in the cells of patients in around 17% of AML cases, which raises questions about the remaining majority of cases. We were able to show that deleting the mouse equivalent of PTPN1 activates a molecule called STAT3, which is important to regulating cell growth and division.

If a patient has too much STAT3, it leads to the generation of too many immature myeloid cells – that hallmark of AML I mentioned earlier. This is potentially a very useful finding for further studies into the genetics behind the disease: in the two other most common mutations linked to AML, which relate to a protein called JAK2 and a receptor called FLT-3, STAT3 is also over-activated. In all, STAT3 is relevant to maybe three quarters of all AML cases. Uncovering exactly how they relate looks critical to developing an eventual cure.

The future

In short, we're closing in on understanding the links between PTPN1, STAT3 and AML. A few years from now, as the cost of genome sequencing falls, it will become a question of identifying which combination of mutations has affected a patient and prescribing a treatment accordingly.

This treatment will probably be more bespoke chemotherapy for that can tolerate it, and perhaps gene editing using tools such as CRISPR for those that cannot. Doctors would edit the correct versions of genes like PTPN1 back into the patient's bone marrow, potentially restoring normal function and negating the often difficult search for a compatible donor.

There is much research still to be done. We need to understand what PTPN1 is doing in healthy myeloid cells to grasp which processes are disturbed when it becomes deleted. The other big question is whether instead of getting deleted, PTPN1 sometimes more subtly mutates and how this relates to AML. Besides this, there are many other genes on the Del20q deletion that we need to better understand, too.

In the meantime, showing that removing PTPN1 leads to AML is an important piece of the puzzle. It brings the day closer when survival rates for AML make the same climb that we have seen in other kinds of leukaemia, and hopefully even beyond.

Explore further: Leukaemia treatment can be made more effective by using a drug for iron overload

Related Stories

Leukaemia treatment can be made more effective by using a drug for iron overload

December 21, 2017
Chemotherapy for one type of leukaemia could be improved by giving patients a drug currently used to treat an unrelated condition, new research shows.

Blocking key pathways is a way to defeat cancer stem cells

October 25, 2017
Scientists from the RIKEN Center for Integrative Medical Sciences in Japan and international collaborators have found that in humanized mice, a cocktail of drugs blocking certain key pathways is effective in eliminating acute ...

The HLF-gene controls the generation of our long-term immune system

November 22, 2017
A research group at Lund University in Sweden has found that when the HLF (hepatic leukemia factor) gene –which is expressed in immature blood cells – does not shut down on time, we are unable to develop a functional ...

Study leads to breakthrough in better understanding acute myeloid leukemia

May 23, 2017
A study led by the University of Birmingham has made a breakthrough in the understanding of how different genetic mutations cause acute myeloid leukaemia.

New leukemia gene stops blood cells 'growing up'

September 14, 2015
Scientists have identified a gene - FOXC1 - that, if switched on, causes more aggressive cancer in a fifth of acute myeloid leukaemia (AML) patients, according to a Cancer Research UK study published in the journal Cancer ...

Researchers found new clue to fighting acute myeloid leukaemia

March 29, 2016
A study led by researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) has uncovered a new clue that may help fight acute myeloid leukaemia (AML), the most ...

Recommended for you

Study tracks evolutionary transition to destructive cancer

February 23, 2018
Evolution describes how all living forms cope with challenges in their environment, as they struggle to persevere against formidable odds. Mutation and selective pressure—cornerstones of Darwin's theory—are the means ...

Researchers use a molecular Trojan horse to deliver chemotherapeutic drug to cancer cells

February 23, 2018
A research team at the University of California, Riverside has discovered a way for chemotherapy drug paclitaxel to target migrating, or circulating, cancer cells, which are responsible for the development of tumor metastases.

Lab-grown 'mini tumours' could personalise cancer treatment

February 23, 2018
Testing cancer drugs on miniature replicas of a patient's tumour could help doctors tailor treatment, according to new research.

An under-the-radar immune cell shows potential in fight against cancer

February 23, 2018
One of the rarest of immune cells, unknown to scientists a decade ago, might prove to be a potent weapon in stopping cancer from spreading in the body, according to new research from the University of British Columbia.

Putting black skin cancer to sleep—for good

February 22, 2018
An international research team has succeeded in stopping the growth of malignant melanoma by reactivating a protective mechanism that prevents tumor cells from dividing. The team used chemical agents to block the enzymes ...

Cancer risk associated with key epigenetic changes occurring through normal aging process

February 22, 2018
Some scientists have hypothesized that tumor-promoting changes in cells during cancer development—particularly an epigenetic change involving DNA methylation—arise from rogue cells escaping a natural cell deterioration ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.