How a formidable leukemia subverts blood stem cells

New findings open a path for developing desperately needed therapies for the most frequently diagnosed leukemia in adults.

 

Leukemia paves the way for its deadly advance by manipulating the micro-environment within the bone marrow, triggering changes that suppress healthy, blood-forming stem cells while favoring the growth of cancer. The loss of hematopoietic stem cells results in bleeding, shortness of breath, fatigue, and infections.

Researchers led by OHSU’s Peter Kurre, M.D., now have uncovered one of the specialized weapons deployed by acute myeloid leukemia to subvert hematopoietic stem cells. The cancer cells secrete membrane-bound vesicles, or exosomes, that are loaded with microRNA molecules that target and disrupt a pivotal control system in the blood-forming stem cells.

kurre
Peter Kurre, M.D.

“This is the first description of a direct interaction between the cancer and hematopoietic stem cells,” says Kurre, who has joint appointments in the Department of Pediatrics and the Department of Cell, Developmental and Cancer Biology.

Kurre and colleagues analyzed the contents of exosomes from AML cells and found an abundance of two specific microRNAs, miR-150 and miR-155, which target a transcription factor, called c-MYB, that’s involved in the differentiation and proliferation of hematopoietic stem cells. Further experiments turned up evidence that exosome-delivered microRNAs also indirectly manipulate the actions of several proteins with established roles in malignancy and blood formation.

The findings open a new path for seeking therapies to protect hematopoietic stem cells and save patients from complications and the need for blood transfusions and hospital admissions. The need is dire. AML is the most frequently diagnosed leukemia in adults, and less than a third of newly diagnosed patients survive beyond five years. The best available treatment is based on a drug combination established as the standard of care more than 30 years ago.

The paper, AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB, appears in Science Signaling. The work was supported in part by a grant from Hyundai Hope on Wheels.

The authors include Kurre lab members Noah Hornick (co-first author), Ben Doron (co-first author), Sherif Abdelhamed, Kianya Huan, and Santhosh Chakkaramakkil Verghese; OHSU faculty members Christina Harrington and Xiaolu Cambronne; and Rongkun Shen from the College at Brockport, State University of New York.