Therapy & molecular genetics of leukaemia in infants

Therapy & molecular genetics of leukaemia in infants

Funding: Triennial Block Grant
(2012–2015)
Researcher: Professor Ursula R Kees

Babies diagnosed with leukaemia face a dismal outlook. This is in sharp contrast with leukaemia in children who are older than 12 months at the time of diagnosis. Some of them achieve a 5-year survival of 95%. Strikingly, in leukaemia patients less than 3 months at the time of diagnosis, the survival rate is only 30%. In an attempt to find better therapy for these patients, international study groups conducted many studies, and the babies were given more intensive therapy. Unfortunately, this led to a large number of toxic deaths, and did not improve overall survival. We urgently need to find novel therapy for these patients. Since treatments using highly toxic chemotherapies are not successful, understanding the biology of this disease holds the key.

In this study, we investigated the genetic features of the leukaemia cells from babies. We have performed genetic analyses using state-of-the art next generation sequencing technology, referred to as RNA-sequencing and exome sequencing. We gained novel insight into which genes are involved, their contribution to disease progression and drug resistance. We confirmed that a gene called MLL is not in its normal position on the chromosome, but is translocated, such that it is next to another chromosome. These translocations are known to confer poor prognosis for patients. We also found that infant patients inherited extremely rare versions (called polymorphisms) in other genes that are known to play a role in cancer. Importantly, these molecular studies identified several known cancer-causing genes, as well as changes to other genes. Many of these altered genes can be targeted by modern therapies to improve treatments of patients with infant leukaemia.

We used the leukaemia specimens from the patients to generate cell lines, such that the cells can be kept alive in the laboratory, which in turn allows us to do study which drugs may be killing the leukaemia cells. We have generated a panel of eight cell lines and used the same methods to analyse the genetic features as were used on the cells from the patients. This confirmed that the cell lines showed the identical translocations of the MLL gene as the ones found in the leukaemia cells from the patients. We then screened the panel of cell lines against 150 approved cancer drugs, which is the first comprehensive assessment that examined the drug response in leukaemia cells from babies. The information obtained clearly showed that some of the currently used drugs do not kill the leukaemia cells (e.g. Mercaptopurine and Methotrexate), while others were very effective, yet not used in contemporary protocols for patients (e.g. Romidepsin and Bortezomib).

Importantly, we could show that these drugs enhance the effectiveness of drugs that are currently used in the treatment of leukaemia patients, for example Cytosine Arabinoside. Taken together, these studies have identified drugs that could be useful to treat babies with leukaemia, including established anti-cancer drugs as well as new-generation drugs. These drugs are expected to provide great benefits in the treatment of patients with this disease. We continue our studies to determine how best to combine particular drugs, and examine outcomes in experimental models. Our results have been presented to members of the international study group Children’s Oncology Group and they intend to include our findings in the plans for the next clinical trials.