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
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.
