New research finds patients with a rare type of bone marrow cancer have distinctive epigenetic changes that can activate harmful genes and cause cancer to grow faster.
Chronic myelomonocytic leukaemia, a type of bone marrow cancer, develops slowly and can form when there are too many monocytes, a variation of white blood cells, in the blood. However, patients with this kind of bone marrow cancer can have an ASXL 1 genetic mutation which can transform the disease into more aggressive acute myeloid leukaemia.
The findings have the potential to clarify a therapeutic strategy and add more depth to the knowledge of ASXL 1 gene expression.
The development of bone marrow cancer
Epigenetics is the chemical modifications of a cell’s genetic material that control how genes are expressed and affect the interpretation of the DNA code. Research has shown that epigenetics plays a key role in the development and progression of many diseases, including cancer.
“The epigenome in patients with these ASXL1 gene mutations is changed in a way that allows the cancer cells to switch on genes that are detrimental to the patients,” said Moritz Binder M.D., a Mayo Clinic haematologist and scientist, and the lead author of the study. Dr Binder is a 2021 Gerstner Family Career Development awardee.
“These epigenetic changes don’t affect the DNA blueprint itself,” Dr Binder explained. “It affects how to the blueprint is read – which pages to read and which pages not to read.”
Nearly 40% of patients have a genetic mutation
Chronic myelomonocytic leukaemia is a bone marrow cancer that typically affects people aged 60 and older. It starts in blood-forming cells of the bone marrow and invades the blood. Nearly 40% of patients with chronic myelomonocytic leukaemia have a mutation in the ASXL1 gene.
“Unfortunately, patients with ASXL1 mutations do not fare well and do not respond as well to the treatments currently available,” Dr Binder said.
For the study, Dr Binder and his team conducted a comprehensive multi-omics interrogation using a variety of high-throughput sequencing methods. Multi-omics offers the opportunity to understand the flow of information that underlies disease.
The researchers compared samples from patients with and without ASXL1 mutations and analysed the activity of genes along with molecules around the DNA. The investigation included gene expression and several modifications affecting the packaging of the DNA.
“This allowed us to perform modelling to draw inference about the effect of epigenetic changes in isolation and in concert on leukemogenic gene expression in ASXL1-mutant chronic myelomonocytic leukaemia,” Dr Binder said.
The researchers discovered that ASXL1 mutations are associated with the overexpression of key genes that drive leukaemia.
“Our study supports the notion that several important leukemogenic driver genes are under the control of regulatory elements in the genome,” Dr Binder said.
The data highlighted that these regulatory elements are only functional in patients with ASXL1-mutant chronic myelomonocytic leukaemia and may lead to new individualised therapeutic targets for this bone marrow cancer. Dr Binder is planning to translate these findings into early phase clinical trials soon.
“Our study is the basis for ongoing work to further explore ways to target these patient-specific regulatory elements with novel small-molecule drugs, ” Dr Binder said. “With this approach, we hope to restore normal gene expression, or at least treat the cancer cells in a new way to overcome the detrimental effect of ASXL1 mutations.”