Mutations can cause this fine-tuning mechanism to malfunction. In the case of the mutation studied by Bousquet, miR-125b is cranked up to 90 times its normal expression.
To see if this overexpression could actually cause leukemia on its own, Bousquet injected into mice fetal liver cells that overexpressed miR-125b. After 16 weeks, the mice showed extremely high miR-125b production. Between 12 and 29 weeks after the transplantation, half of the mice died from one of three types of leukemia: myeloproliferative neoplasm, B-cell acute lymphoblastic leukemia, or T-cell acute lymphoblastic leukemia.
"Because miR-125b can lead to different kinds of leukemia, it's a major cancer-causing miR," says Bousquet. "It's also interesting that overexpression of miR-125b is seen in patients with B-cell lymphoblastic leukemia and myeloid leukemia, so I'm pretty sure we can find overexpression in other leukemias."
After establishing that miR-125b overexpression can cause different leukemias, Bousquet tested whether miR-125b overexpression can also accelerate disease progression. Into mice without any bone marrow, she transplanted bone marrow cells that had either the BCR-ABL mutation or the BCR-ABL mutation with a miR-125b overproduction mutation. The mice with both mutations had a median survival of 21 days, compared with 35 days for the BCR-ABL-only control group, a statistically significant difference.
The two experiments show that miR-125b overexpression can be both the primary cause for leukemia and be a secondary agent that hastens its progression.
Although many of miR-125b's target genes have not yet been identified, Bousquet says they are probably involved in proliferation, and cell maturation.
"This is the problem with microRNAs each miR has many targets," says Bousquet, who will be investigating these targets further. "I would say ther
|Contact: Nicole Giese|
Whitehead Institute for Biomedical Research