The long non-coding RNA CDK6-AS1 overexpression impacts on acute myeloid leukemia differentiation and mitochondrial dynamics

Elena Porcù; Maddalena Benetton; Valeria Bisio; Ambra Da Ros; Claudia Tregnago; Giulia Borella; Carlo Zanon; Matteo Bordi; Giuseppe Germano; Sabrina Manni; Silvia Campello; Dinesh S. Rao; Franco Locatelli; Martina Pigazzi

iScience (Nov 2021)

The long non-coding RNA CDK6-AS1 overexpression impacts on acute myeloid leukemia differentiation and mitochondrial dynamics

Elena Porcù,
Maddalena Benetton,
Valeria Bisio,
Ambra Da Ros,
Claudia Tregnago,
Giulia Borella,
Carlo Zanon,
Matteo Bordi,
Giuseppe Germano,
Sabrina Manni,
Silvia Campello,
Dinesh S. Rao,
Franco Locatelli,
Martina Pigazzi

Affiliations

Elena Porcù: Pediatric Hematology, Oncology and Hematopoietic Cell&Gene Therapy Division of Women's and Children's Health Department, University-Hospital of Padova, Via N. Giustiniani, 3, 35128 Padova, Italy
Maddalena Benetton: Pediatric Hematology, Oncology and Hematopoietic Cell&Gene Therapy Division of Women's and Children's Health Department, University-Hospital of Padova, Via N. Giustiniani, 3, 35128 Padova, Italy
Valeria Bisio: Pediatric Hematology, Oncology and Hematopoietic Cell&Gene Therapy Division of Women's and Children's Health Department, University-Hospital of Padova, Via N. Giustiniani, 3, 35128 Padova, Italy
Ambra Da Ros: Pediatric Hematology, Oncology and Hematopoietic Cell&Gene Therapy Division of Women's and Children's Health Department, University-Hospital of Padova, Via N. Giustiniani, 3, 35128 Padova, Italy
Claudia Tregnago: Pediatric Hematology, Oncology and Hematopoietic Cell&Gene Therapy Division of Women's and Children's Health Department, University-Hospital of Padova, Via N. Giustiniani, 3, 35128 Padova, Italy
Giulia Borella: Pediatric Hematology, Oncology and Hematopoietic Cell&Gene Therapy Division of Women's and Children's Health Department, University-Hospital of Padova, Via N. Giustiniani, 3, 35128 Padova, Italy
Carlo Zanon: Pediatric Onco-Hematology, Stem Cell Transplant and Gene Therapy Laboratory, Istituto di Ricerca Pediatrica - Città della Speranza, 35127 Padova, Italy
Matteo Bordi: Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy; Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, 00143 Rome, Italy
Giuseppe Germano: Pediatric Onco-Hematology, Stem Cell Transplant and Gene Therapy Laboratory, Istituto di Ricerca Pediatrica - Città della Speranza, 35127 Padova, Italy
Sabrina Manni: Department of Medicine, Hematology and Clinical Immunology Branch, University of Padova, Padova, and Veneto Institute of Molecular Medicine (VIMM), 35129 Padova, Italy
Silvia Campello: Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy
Dinesh S. Rao: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA 90095, USA
Franco Locatelli: Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital, Sapienza University of Rome, 00165 Roma, Italy
Martina Pigazzi: Pediatric Hematology, Oncology and Hematopoietic Cell&Gene Therapy Division of Women's and Children's Health Department, University-Hospital of Padova, Via N. Giustiniani, 3, 35128 Padova, Italy; Pediatric Onco-Hematology, Stem Cell Transplant and Gene Therapy Laboratory, Istituto di Ricerca Pediatrica - Città della Speranza, 35127 Padova, Italy; Corresponding author

Journal volume & issue: Vol. 24, no. 11
p. 103350

Abstract

Read online

Summary: Patients with acute myeloid leukemia (AML) carrying high-risk genetic lesions or high residual disease levels after therapy are particularly exposed to the risk of relapse. Here, we identified the long non-coding RNA CDK6-AS1 able to cluster an AML subgroup with peculiar gene signatures linked to hematopoietic cell differentiation and mitochondrial dynamics. CDK6-AS1 silencing triggered hematopoietic commitment in healthy CD34+ cells, whereas in AML cells the pathological undifferentiated state was rescued. This latter phenomenon derived from RUNX1 transcriptional control, responsible for the stemness of hematopoietic precursors and for the block of differentiation in AML. By CDK6-AS1 silencing in vitro, AML mitochondrial mass decreased with augmented pharmacological sensitivity to mitochondria-targeting drugs. In vivo, the combination of tigecycline and cytarabine reduced leukemia progression in the AML-PDX model with high CDK6-AS1 levels, supporting the concept of a mitochondrial vulnerability. Together, these findings uncover CDK6-AS1 as crucial in myeloid differentiation and mitochondrial mass regulation.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

About the journal

Abstract

Keywords