Karsan group identify microRNAs that are important in a maligant blood disease

Characteristic hypolobated dysplastic megakaryocyte seen with loss of miR-145 and miR-146a (right panel) compared to a normal megakaryocyte (left panel). This finding is seen in patients with 5q-syndrome.

A study published in Nature Medicine, led by CBR investigator Aly Karsan, Professor and Medical Director of the Cancer Genetics Laboratory, BCCA, and Head of Clinical Genomic Diagnostics at the Genome Sciences Centre reveals the role of two microRNAs (miRs) in a subtype of myelodysplastic syndromes (MDS). MDS comprise a group of malignant hematopoietic stem cell disorders characterized by dysplastic and ineffective hematopoiesis associated with low circulating blood counts. Patients with MDS progress either to bone marrow failure or acute myeloid leukemia. A partial deletion of the long arm of chromosome 5 is the commonest structural genomic abnormality in MDS. This is associated particularly with macrocytic anemia and megakaryocytic dysplasia, and is referred to as 5q- syndrome.

MicroRNAs are small RNAs, 19 to 25 nucleotides long, that do not code for a protein, but rather function to repress translation of multiple target mRNAs. Dr. Karsan’s group reports that loss of miR-145 and miR-146a, which are encoded on chromosome 5, results in derepression of innate immune signaling pathways. This inappropriate activation of innate immune signaling in hematopoietic stem cells explains the megakaryocytic abnormalities in 5q- syndrome, and also the propensity to progress either to bone marrow failure or acute myeloid leukemia.

Some of the members of Dr. Karsan's lab studying MDS. Left to Right: Dr. Suzanne Vercauteren (former Hematopathology resident); Dr. Dan Starczynowski, post-doctoral fellow; Sandy Sung, technician.

Currently an immunomodulatory drug is used to treat MDS patients with deletions of the long arm of chromosome 5, but it is unclear how the drug functions. Ongoing studies in Dr. Karsan’s laboratory are addressing the mechanism of action of this drug with respect to microRNA expression and innate immune signaling. This work was conducted in collaboration with groups at the Genome Sciences Centre, the Terry Fox Laboratory and investigators at the Sunnybrook Hospital in Toronto.

Get the whole story in Nature Medicine.

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