Loss of expression of both miR-15/16 loci in CML transition to blast crisis

Francesca Lovat; Pierluigi Gasparini; Giovanni Nigita; Karilyn Larkin; John C Byrd; Mark D Minden; Michael Andreeff; Bing Z Carter; Carlo M Croce

doi:10.1073/pnas.2101566118

Loss of expression of both miR-15/16 loci in CML transition to blast crisis

Proc Natl Acad Sci U S A. 2021 Mar 16;118(11):e2101566118. doi: 10.1073/pnas.2101566118.

Authors

Francesca Lovat^{1

2}, Pierluigi Gasparini^{1

2

3}, Giovanni Nigita^{1

2}, Karilyn Larkin^{2

4}, John C Byrd^{2

4}, Mark D Minden⁵, Michael Andreeff⁶, Bing Z Carter⁶, Carlo M Croce^{7

2}

Affiliations

¹ Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH 43210.
² Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210.
³ School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, 2308 NSW, Australia.
⁴ Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
⁵ Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada.
⁶ Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
⁷ Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH 43210; carlo.croce@osumc.edu.

Abstract

Despite advances that have improved the treatment of chronic myeloid leukemia (CML) patients in chronic phase, the mechanisms of the transition from chronic phase CML to blast crisis (BC) are not fully understood. Considering the key role of miR-15/16 loci in the pathogenesis of myeloid and lymphocytic leukemia, here we aimed to correlate the expression of miR-15a/16 and miR-15b/16 to progression of CML from chronic phase to BC. We analyzed the expression of the two miR-15/16 clusters in 17 CML patients in chronic phase and 22 patients in BC and in 11 paired chronic phase and BC CML patients. BC CMLs show a significant reduction of the expression of miR-15a/-15b/16 compared to CMLs in chronic phase. Moreover, BC CMLs showed an overexpression of miR-15/16 direct targets such as Bmi-1, ROR1, and Bcl-2 compared to CMLs in chronic phase. This study highlights the loss of both miR-15/16 clusters as a potential oncogenic driver in the transition from chronic phase to BC in CML patients.

Keywords: blast crisis; chronic myeloid leukemia; miR-15/16 cluster.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Blast Crisis / genetics
Blast Crisis / pathology*
Disease Progression
Female
Gene Expression Regulation, Leukemic
Genetic Loci
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
Male
MicroRNAs / genetics*
Middle Aged
Polycomb Repressive Complex 1 / genetics
Polycomb Repressive Complex 1 / metabolism
Proto-Oncogene Proteins c-bcl-2 / genetics
Proto-Oncogene Proteins c-bcl-2 / metabolism
Receptor Tyrosine Kinase-like Orphan Receptors / genetics
Receptor Tyrosine Kinase-like Orphan Receptors / metabolism

Substances

BCL2 protein, human
BMI1 protein, human
MIRN15 microRNA, human
MIRN16 microRNA, human
MicroRNAs
Proto-Oncogene Proteins c-bcl-2
Polycomb Repressive Complex 1
ROR1 protein, human
Receptor Tyrosine Kinase-like Orphan Receptors

Abstract

Publication types

MeSH terms

Substances

Grants and funding