SWCRF researchers identify a

micro-RNA that promotes the onset of CML and Down Syndrome AML.

 

Ravi Bhatia, M.D. John Crispino, Ph.D. Shai Izraeli, M.D.
UAB Comprehensive Cancer Center Northwestern University Sheba Medical Center, Tel Aviv University

 

The Samuel Waxman Cancer Research Foundation’s collaborative model of scientific investigation made new strides in leukemia research with the publication of two papers centering on a microRNA that blocks cell maturation in the February issue of the leading science journal Blood, a publication of the American Society of Hematology. 

Ravi Bhatia, M.D., of UAB Comprehensive Cancer Center, Shai Izraeli, M.D., of the Sheba Medical Center at Tel Aviv University, and John Crispino, Ph.D., of Northwestern University, authored papers examining the role of miRNA 486, a regulator of blood cell differentiation, in the development of chronic myeloid leukemia (CML) and Down Syndrome AML. miRNA 486 was previously shown to regulate muscle development and these papers are the first descriptions of its involvement in blood cancer. 

While attending the Waxman Foundation’s scientific review in New York City last May, Drs. Bhatia and Izraeli discovered they were investigating the same microRNA, which is a cellular RNA fragment that prevents the production of a particular protein by binding to and destroying the messenger RNA that would have produced the protein.  They shared their findings on miRNA 486 and submitted their papers to Blood simultaneously, Dr. Izraeli’s paper including contributions from his collaborator in pediatric cancer research Dr. Crispino, among other scientists, resulting in a powerful showcase for their respective theories. 

miRNA 486 in CML

Dr. Bhatia’s work, completed during his tenure at City of Hope, found that miRNA 486 is significantly upregulated in CML compared with normal blood cells. The effects of miRNA 486 on blood cell growth and survival are mediated at least in part via regulation of signaling that blocks cell death and the expression of the transcription factor FOXO1. The researchers identified several novel miRNA 486 target genes that may modulate the differentiation of red blood cells. They further showed that increased expression of miRNA 486 in CML progenitors is related to both kinase-dependent and kinase-independent mechanisms. Treatment with the kinase inhibitor Imatnib combined with microRNA inhibition reduced CML progenitor growth and enhanced cell death.

miRNA 486 in Down Syndrome AML

The paper by Drs. Izraeli and Crispino examined the role of miRNA 486 in ML-DS, a subtype of myeloid leukemia for which children with Down Syndrome are especially at risk. This microRNA, facilitated by mutation in the GATA1 protein, enhances the aberrant traits of the AML’s red blood cells and promotes the survival of the pre-leukemic and leukemic cells. These back-to-back findings further elucidate the provocative role – and destructive impact -- of this cellular fragment in the formation of these blood malignancies.

The findings in both papers have some potential general implications. Both research groups identified a cancer growth pathway, AKT, activated by miRNA 486. Thus miRNA 486 may be a biomarker for blood cancers that may benefit from targeted therapy by anti-AKT drugs. The researchers also discovered that miRNA-486 is important in the development of red blood cells. Hence it is possible that in the future abnormalities in this miRNA will be discovered in human diseases of the red blood cells such as anemias and polycythemias.

About the Researchers:

Shai Izraeli, M.D., is Head of Functional Genomics and Childhood Leukemia and Cancer Research and a senior physician of the Department of Pediatric Hemato-Oncology at the Edmond and Lily Safra Childhren’s hospital at the Sheba Medical Center. He is also  the Giorgio and Dora Shapiro Professor of Hematological Malignancies at Sackler Medical School and the Molecular Genetics and Biochemistry department at Tel Aviv University.

John Crispino, Ph.D., is Professor of Medicine, Robert I. Lurie, MD, and Lora S. Lurie Professor, Feinberg School of Medicine
Associate Director of Education, at the Robert H Lurie Comprehensive Cancer Center.

Ravi Bhatia, Ph.D., is Professor in the Department of Medicine and Director of the Division of Hematology and Oncology and Deputy Director of the UAB Comprehensive Cancer Center at the University of Alabama.