A groundbreaking new publication by Dr. John Dick’s TFRI-funded team has confirmed that miRNA expression patterns are predictive of disease outcome in leukemia, and play a powerful role in governing the fundamental properties that define the “stemness” state of human leukemia stem cells (LSCs).
Published in Cancer Cell (February 2016), the present study generated a prognostic LSC-associated miRNA signature derived from functionally validated subpopulations of acute myeloid leukemia (AML) samples to investigate miRNA function in human AML stem cells. This was a unique idea in the literature. While over 2,500 validated human miRNA have been identified in our genome, there exists a lack of rigorous studies investigating the role of miRNA in either human hematopoietic stem cell (HSCs) or LSCs.
Unlike other types of leukemia that have fairly high cure rates, AML’s prognosis is still very grim for certain subtypes. Since LSCs are an important reservoir of disease relapse in AML, understanding LSCs more completely at the molecular level in order to design improved and specific therapies to target these cells is critical for patient outcome.
The study’s findings suggested that a small non-coding RNA, miR-126, is a highly expressed biomarker of both HSCs and LSCs. Further, despite the miRNA targeting the same proteins in these cells the functional outcome is opposite, whereby increasing the expression of miR-126 in HSCs and LSCs leads to the loss and increase in these cells respectively.
Leukemia stem cells play central roles in disease progression and recurrence due to their intrinsic capacity for self-renewal and chemotherapy resistance. However, few regulators of human LSCs function are known. The present study established that miRNA played a powerful role in governing the fundamental properties that define the stemness state of human LSCs including quiescence, self-renewal, and chemotherapy response. Further, looking forward it may be possible to therapeutically target the networks that specifically control LSC through perturbation of miR-126 levels.
Study: miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells.
Authors: Eric R. Lechman, Bernhard Gentner, Stanley W.K. Ng, Jean C.Y. Wang, Luigi Naldini, John E. Dick.
Funding: This work was supported by grants to L.N. from Telethon (TIGET grant), EU (FP7 GA 222878 PERSIST, ERC Advanced Grant 249845 TARGETING GENE THERAPY), and the Italian Ministry of Health and to J.E.D. from the Canadian Institutes of Health Research, Canadian Cancer Society, Terry Fox Foundation, Genome Canada through the Ontario Genomics Institute, Ontario Institute for Cancer Research with funds from the Province of Ontario, and a Canada Research Chair.
Reported in TFRI Links, Issue 1, Fall 2016