In brief

Digitized colored light micrograph of cancerous blood cells in chronic myeloid leukemia (CML).

© Science Photo Library

Reversing a cancer crisis

13 Nov 2020

Researchers have pieced together a series of molecular events that trigger the progression of chronic myeloid leukemia to its acute phase—the ‘blast crisis.’

Unlike most types of cancer, which are assigned a stage based on tumor size and extent of spread, chronic myeloid leukemia (CML), a disease of the bone marrow, is measured by the number of immature white blood cells in the blood or bone marrow, which are commonly known as ‘blasts.’

According to a system proposed by the World Health Organization, patients in the chronic phase have less than 10 percent blasts in their blood or bone marrow, and usually respond to standard treatment. Patients in the accelerated phase have 15 to 30 percent blasts, while patients in the acute phase—or ‘blast crisis’—have 20 percent or more blasts, some of which would have spread to other organs.

“CML patients in the blast-crisis phase no longer respond to the canonical treatment and have a poor prognosis. In particular, because of its rarity and daunting molecular heterogeneity, physicians quickly run out of effective treatment options,” explained Axel Hillmer, an Adjunct Group Leader at A*STAR’s Genome Institute of Singapore (GIS).

Hillmer, together with GIS colleague Asif Javed and Sin Tiong Ong at Duke-NUS Graduate Medical School Singapore, decided to map out a clinically relevant molecular model of CML transformation to blast crisis, which may help in identifying effective treatments and novel biomarkers for the disease.

Access to a rare cohort of 13 paired samples from patients who had progressed from the chronic phase to blast crisis provided an opportunity for the research team to study the samples using large scale ‘-omics’ approaches, ranging from whole genome and exome sequencing to chromatin immunoprecipitation and high-throughput sequencing.

Using transcriptome analysis, they found that the blast-crisis genome was significantly enriched for changes involving components of the polycomb repressive complex (PRC) pathway, regardless of the genetic background of the cells studied.

In blast-crisis samples, PRC1 mutations were shown to silence novel tumor suppressor genes, such as NR4A2, promoting cell survival and proliferation. PRC2 mutations, on the other hand, were shown to silence key genes involved in myeloid differentiation and tumor suppressor function by DNA hypermethylation, in a process called ‘epigenetic switching.’

One hypothesis is that patients with a poor prognosis can be reverted to a lower risk category by inducing the re-expression of PRC-controlled genes. In cell culture experiments, the researchers demonstrated that two PRC inhibitors—decitabine and PTC209—both independently lowered the viability of blast-crisis cells. Used in combination, they reduced colony formation by 90 percent, opening up an avenue for combination treatments.

“We found that epigenetic reprogramming is responsible for the transition from benign chronic-phase CML to fatal blast-crisis CML. Our cell culture experiments suggest that epigenetic drugs may improve CML treatment, but its efficacy remains to be determined in clinical studies,” Hillmer said.

The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore (GIS).

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Ko, T.K., Javed, A., Lee, K.L., Pathiraja, T.N., Liu, X., et al. An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia. Blood 135 (26), 2337-2353 (2020) | article

About the Researcher

Axel Hillmer obtained his PhD degree in Biology from the University of Bonn, Germany. In 2008, he joined A*STAR’s Genome Institute of Singapore (GIS), where he started work on cancer genomics. He established his own group in 2011, focusing on genomic changes that contribute to cancer development, disease progression and treatment resistance. Hillmer moved back to Germany in 2016 but remains affiliated with GIS as an Adjunct Group Leader.

This article was made for A*STAR Research by Wildtype Media Group