According to NCI, there are well over 300 ongoing clinical trials for acute myeloid leukemia (AML). AML is an important disease model to our understanding of how epigenetics fits into the multidimensional cancer process. Please find below a description of AML, and a few recent important studies providing traction on AML sub-type biomarkers and drug targets using epigenetic techniques.
AML is a blood and marrow cancer. Myeloid stem cells abnormally propagate and differentiate into non-functional red blood cell, white blood cell, or platelets. Clinical sub-typing is currently based on the degree of derivation from normal cells microscopically, and by cytogenic methods. Adult AML is diagnosed when 20% or greater leukemia cells appear in the bone marrow. Keep in mind, this cancer can progress, re-occur and metastasize. The worst outcomes involve tumors in neural tissue. Current treatments include chemotherapy and radiation, which can be followed by stem cell transplantation. About 25% of adult AML patients who go into complete remission following treatment, survive for 3+ years and can be cured.
Thankfully, there’s a lot of good work coming out. Let’s hope the research below, will lead to translational medicine to improve those outcomes.
- Last week in Nature, RNAi screen identifies BrD4 as a therapeutic target in acute myeloid leukaemia (August 2011) Zuber et al. shows how RNAi screening methods can be used for identifying new AML specific drug targets. The authors promote “direct modulation of epigenetic machinery” as a general strategy. Brd4 previously had no known function in leukemia. (It’s known function was to bind to acetylated histones). I can’t wait to see how this group will push these findings to the next level. The group also published a Nature Biotechnology paper describing their RNAi workflow.
- This video is of Dr. Maria Figueroa giving a talk at BTG2011, she is an author of Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation (2010) Cancer Cell, and Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation (2011) Cancer Cell Moran-Crusio, K. et al. She explains work by her NYU lab and collaborators’ , that DNA methylation profiling identifies clinically relevant AML subtypes, which gene expression and cytogenic studies can not. Additionally, their work shows that dysregulation of epigenetic machinery can occur directly by a mutated metabolic enzyme.
- This study, Stem cell gene expression programs influence clinical outcome in human leukemia. Eppert et al. (August 2011) Nature Medicine, uses gene expression profiling for identifying AML clinical outcomes, and promotes the cancer stem cell model.
Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA, Magoon D, Qi J, Blatt K, Wunderlich M, Taylor MJ, Johns C, Chicas A, Mulloy JC, Kogan SC, Brown P, Valent P, Bradner JE, Lowe SW, & Vakoc CR (2011). RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature PMID: 21814200