ADVERTISEMENT

Molecular Analysis Of Leukemia Patients By Next Generation Sequencing Predicts Targeted Therapy Outcome

Imatinib (Gleevec/Glivec, Novartis Pharma) is an oral drug developed to fight a particular type of blood cancer, termed Chronic Myeloid Leukemia (CML), in which there is an abnormal expansion of white blood cells number.

At the molecular level, CML is caused by the formation of an aberrant chromosome, called the Philadelphia chromosome (Ph), which contains a ‘chimaeric’ gene derived from the fusion of two normal genes: BCR/ABL. This fusion gene tells the cells to divide in an uncontrolled manner, leading to leukemia. Imatinib was designed to block the activity of BCR/ABL inside the cells, in a specific way, like a key in the lock: BCR/ABL needs ATP to function, and imatinib occupies the space where ATP would bind, therefore blocking the enzyme activity.

ADVERTISEMENT

 

Before imatinib, CML was a deadly disease, with a clinical course that clinicians used to divide into three phases: a long, indolent chronic phase followed by a short transition period (accelerated phase) and a final rapid acute phase termed blast crisis, which invariably led to death, unless the patient could undergo bone marrow transplant. Imatinib revolutionized the treatment and the outcome of CML: patients diagnosed in 2017 can expect a normal lifespan, while taking a pill a day, with very limited side effects.

Unfortunately, not all patients do well, even under imatinib. In some cases, the BCR/ABL gene mutates to a drug-resistant version and the disease reappears. New, more potent drugs have been developed to fight back such resistant leukemia.

In a recent paper, we analyzed a cohort of CML patients by Next Generation Sequencing. We sequenced the DNA from their leukemic cells at diagnosis and compared it with that from normal cells. We found that, in addition to the well-known BCR/ABL fusion gene, these patients had multiple other mutations in their cancer.

ADVERTISEMENT

In order to make sense of this finding, we tried to prioritize mutations according to a novel score that we developed in the lab, the OncoScore (OS). This tool gives a score to any gene by looking in the medical literature: the more a certain gene is associated with keywords such as ‘cancer’ or ‘leukaemia’ in peer-reviewed papers, the higher its score is. We previously demonstrated that genes with OS>22 can be considered as potential oncogenes.

Interestingly, when we correlated the score of our patients mutations with their clinical response to imatinib therapy, we found that patients having higher scores had a higher probability to fail imatinib treatment, thus suggesting that additional somatic mutations in CML can modify the response to imatinib, although BCR/ABL is still the main driver of the disease. As the OS is a gene score, we compared patients carrying several mutated genes by using three ‘patient-level’ scores: the total OS (tOS), which is the sum of OncoScores of all the identified mutations in a patient; the sum of OS values considering only those genes passing the oncogene threshold (OS22 score); or by 2topOS, which is the sum of scores from the two highest-ranking mutated genes in each patient.

All patient scores yielded the same result: imatinib-resistant patients had significantly higher scores compared to responding patients, after a median of 5 years in therapy. Interestingly, the widely used Sokal score (a scoring method based on clinical parameters) was not able to discriminate the two populations, indicating that molecular profiling can be superior to traditional clinical stratification in these patients.

This study, Somatic mutations identified at diagnosis by exome sequencing can predict response to imatinib in chronic phase chronic myeloid leukemia (CML) patients was recently published in the American Journal of Hematology.

ADVERTISEMENT

Comments

READ THIS NEXT

Twinning Boundary ω-Fe Makes Carbon Martensite Hard In Steels

People have used steel over 3000 years. Steel supports our daily life, a world without steel would be a very […]

Small-Scale Or Industrial Plantations? Consumers Must Choose Wisely: Which Oil Palm Production System Can Better Protect Biodiversity?

Tropical rainforest landscapes are threatened by the industrial agricultural expansion, which leads to forest fragmentation and habitat loss. The remaining […]

Traitorous Eyes

A twin study suggests that DNA also controls how well one can spot thoughts and emotions in the eyes of […]

The Performance Of A Vanadium Redox Flow Battery With Non-Uniformly Compressed Electrodes

Electrical energy storage technologies are an important solution for a mismatched problem between the distributed intermittent power generation (like solar […]

Where Does Translation Take Place In A Cell?

Cells perform many different functions. They produce energy, communicate with other cells, and compose the physical bulk of the body. […]

Organ Cryopreservation: Nature’s Protocol For Freezing Organs

Every year in Canada, 1600 people are added to the organ transplant waiting list, but there are only 20.9 donors […]

Mental Fatigue Impairs Gait Performance In Old Adults: A New Risk Factor For Falls In The Elderly?

Everyone knows the sensations which arise after hours of driving a car or focused working in front of a screen. […]

Science Trends is a popular source of science news and education around the world. We cover everything from solar power cell technology to climate change to cancer research. We help hundreds of thousands of people every month learn about the world we live in and the latest scientific breakthroughs. Want to know more?