Cell Reports (Mar 2022)
Identification of the global miR-130a targetome reveals a role for TBL1XR1 in hematopoietic stem cell self-renewal and t(8;21) AML
- Gabriela Krivdova,
- Veronique Voisin,
- Erwin M. Schoof,
- Sajid A. Marhon,
- Alex Murison,
- Jessica L. McLeod,
- Martino M. Gabra,
- Andy G.X. Zeng,
- Stefan Aigner,
- Brian A. Yee,
- Alexander A. Shishkin,
- Eric L. Van Nostrand,
- Karin G. Hermans,
- Aaron C. Trotman-Grant,
- Nathan Mbong,
- James A. Kennedy,
- Olga I. Gan,
- Elvin Wagenblast,
- Daniel D. De Carvalho,
- Leonardo Salmena,
- Mark D. Minden,
- Gary D. Bader,
- Gene W. Yeo,
- John E. Dick,
- Eric R. Lechman
Affiliations
- Gabriela Krivdova
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A5, Canada
- Veronique Voisin
- The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
- Erwin M. Schoof
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
- Sajid A. Marhon
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
- Alex Murison
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
- Jessica L. McLeod
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
- Martino M. Gabra
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Andy G.X. Zeng
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A5, Canada
- Stefan Aigner
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA
- Brian A. Yee
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA
- Alexander A. Shishkin
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA
- Eric L. Van Nostrand
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA
- Karin G. Hermans
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Program of Developmental & Stem Cell Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G0A4, Canada
- Aaron C. Trotman-Grant
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
- Nathan Mbong
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
- James A. Kennedy
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Division of Medical Oncology and Hematology, Sunnybrook Health Sciences Centre, Toronto, ON M4N3M5, Canada
- Olga I. Gan
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
- Elvin Wagenblast
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
- Daniel D. De Carvalho
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1A8, Canada
- Leonardo Salmena
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Mark D. Minden
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
- Gary D. Bader
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A5, Canada; The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5T 3A1, Canada
- Gene W. Yeo
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA
- John E. Dick
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A5, Canada; Corresponding author
- Eric R. Lechman
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Corresponding author
- Journal volume & issue
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Vol. 38,
no. 10
p. 110481
Abstract
Summary: Gene expression profiling and proteome analysis of normal and malignant hematopoietic stem cells (HSCs) point to shared core stemness properties. However, discordance between mRNA and protein signatures highlights an important role for post-transcriptional regulation by microRNAs (miRNAs) in governing this critical nexus. Here, we identify miR-130a as a regulator of HSC self-renewal and differentiation. Enforced expression of miR-130a impairs B lymphoid differentiation and expands long-term HSCs. Integration of protein mass spectrometry and chimeric AGO2 crosslinking and immunoprecipitation (CLIP) identifies TBL1XR1 as a primary miR-130a target, whose loss of function phenocopies miR-130a overexpression. Moreover, we report that miR-130a is highly expressed in t(8;21) acute myeloid leukemia (AML), where it is critical for maintaining the oncogenic molecular program mediated by the AML1-ETO complex. Our study establishes that identification of the comprehensive miRNA targetome within primary cells enables discovery of genes and molecular networks underpinning stemness properties of normal and leukemic cells.
