Results from a study conducted by St. Jude Children’s Research Hospital and the Munich Leukemia Laboratory were presented today as a late-breaking abstract at the American Society of Hematology annual meeting. The study integrates genomic and transcriptomic sequencing to provide the most detailed classification of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) to date. The researchers conducted whole genome sequencing and transcriptome sequencing (RNA-seq) on 598 adults with AML and 706 with MDS. The researchers found evidence to support several different biologic subgroups. They found sets of mutations that cooperate to drive the development of leukemia and predict poor outcomes as well as groups of mutations that indicate positive responses to treatment.
Ilaria Iacobucci, Ph.D., of the St. Jude Department of Pathology, explained: “These diseases have a complex genomic background that clinicians cannot ignore if they want to treat these patients optimally. Therapy for AML has changed little in the last five decades so we need to better understand the nature of genomic changes in order to offer new therapies to these patients. Our understanding of the genetics of these diseases has advanced dramatically in the last decade due to intensive sequencing efforts. However, most of these studies used a targeted sequencing-based approach or were limited to specific subtypes. Now, by integrating whole genome and transcriptome sequencing, researchers can further unravel the biology of these diseases.
AML and MDS are similar since they both derive from aberrations occurring in hematopoietic stem cells and cause impaired differentiation. However, the diseases differ in immature white blood cell (blast) counts and cell morphology. The researchers wanted to learn more about how the diseases divide into genetic subgroups to inform treatments based on their biology. The findings demonstrate how different mutation patterns contribute to the growth of leukemia cells. For example, prognosis is generally considered quite good for patients whose disease has an NPM1 mutation. The researchers found that this subgroup can be further divided based on the presence of other mutations to indicate who is most likely to have a favorable response and thus might not require as stringent a treatment regimen.
The work also reveals a new finding regarding AML fueled by RUNX1 mutations. These mutations have only provisionally been considered a distinct subgroup by WHO classification. Yet, the new results show that RUNX1 AML is a distinct subtype with a poor prognosis. But there is more: another collaborative research effort by Australian and US scientists has led to the discovery of a promising new approach to treating some of the worst types of leukaemia, including an aggressive leukaemia that mostly affects babies. This is called MLL-rearranged leukaemia (MLL-r) which is a subtype of leukaemia that has a particular genetic structure known as MLL rearrangement. This occurs in about 80% of acute leukemia cases in infants (children under 1 year of age) and up to 10% of all leukemia cases, including acute lymphoblastic (ALL) and acute myeloid leukemia (AML).
Often resistant to chemotherapy and extremely difficult to treat, MLL-r leukaemia claims the lives of many of those affected, while those who survive are often left with serious long-term effects due to the highly intensive treatment they are given. The new research, to be published this month in the international journal Cancer Cell, describes a new therapy developed for MLL-r leukaemia as having ‘outstanding pharmaceutical properties.’ The newly developed agent, a small molecule inhibitor called VTP50469, is one of a new breed of targeted therapies, named for the fact that they are designed to specifically target molecules that are critical for the survival and growth of cancer cells. Such therapies offer significant advantages over conventional drug treatments, since as well as being more effective, they cause far fewer side effects.
In the case of MLL-r leukaemia, the targeted proteins are Menin and MLL fusion chimaeras, which interact in leukaemia cells to drive the malignant growth of the cells. Professor Richard Lock, Head of the Blood Cancers Theme at Children’s Cancer Institute, Australia, deems that new therapeutic approaches are desperately needed for MLL-r leukaemia. The combination of drugs currently used for treatment is often not effective and causes significant side effects. This is undesirable in anyone, but is particularly a problem in children, whose growing bodies are very susceptible to the damaging effects of toxic drugs.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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