Myeloid leukemia vulnerabilities embedded in long noncoding RNA locus MYNRL15

Michelle Ng; Lonneke Verboon; Hasan Issa; Raj Bhayadia; Marit Willemijn Vermunt; Robert Winkler; Leah Schüler; Oriol Alejo; Konstantin Schuschel; Eniko Regenyi; Dorit Borchert; Michael Heuser; Dirk Reinhardt; Marie-Laure Yaspo; Dirk Heckl; Jan-Henning Klusmann

doi:10.1016/j.isci.2023.107844

Myeloid leukemia vulnerabilities embedded in long noncoding RNA locus MYNRL15

iScience. 2023 Sep 7;26(10):107844. doi: 10.1016/j.isci.2023.107844. eCollection 2023 Oct 20.

Authors

Michelle Ng¹, Lonneke Verboon^{2

3

4}, Hasan Issa^{2

3

4}, Raj Bhayadia^{2

3

4}, Marit Willemijn Vermunt^{2

4}, Robert Winkler^{2

3

4}, Leah Schüler^{2

3

4}, Oriol Alejo¹, Konstantin Schuschel^{2

3

4}, Eniko Regenyi^{1

5}, Dorit Borchert⁶, Michael Heuser⁷, Dirk Reinhardt⁸, Marie-Laure Yaspo⁵, Dirk Heckl⁹, Jan-Henning Klusmann^{2

3

4}

Affiliations

¹ Department of Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany.
² Department of Pediatrics, Goethe University Frankfurt, 60323 Frankfurt (Main), Germany.
³ Frankfurt Cancer Institute, Goethe University Frankfurt, 60323 Frankfurt (Main), Germany.
⁴ German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz and German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵ Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
⁶ Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany.
⁷ Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany.
⁸ Clinic for Pediatrics III, University Hospital Essen, 45147 Essen, Germany.
⁹ Institute for Experimental Pediatric Hematology and Oncology, Goethe University Frankfurt, 60323 Frankfurt (Main), Germany.

Abstract

The noncoding genome presents a largely untapped source of new biological insights, including thousands of long noncoding RNA (lncRNA) loci. While lncRNA dysregulation has been reported in myeloid malignancies, their functional relevance remains to be systematically interrogated. We performed CRISPRi screens of lncRNA signatures from normal and malignant hematopoietic cells and identified MYNRL15 as a myeloid leukemia dependency. Functional dissection suggests an RNA-independent mechanism mediated by two regulatory elements embedded in the locus. Genetic perturbation of these elements triggered a long-range chromatin interaction and downregulation of leukemia dependency genes near the gained interaction sites, as well as overall suppression of cancer dependency pathways. Thus, this study describes a new noncoding myeloid leukemia vulnerability and mechanistic concept for myeloid leukemia. Importantly, MYNRL15 perturbation caused strong and selective impairment of leukemia cells of various genetic backgrounds over normal hematopoietic stem and progenitor cells in vitro, and depletion of patient-derived xenografts in vivo.

Keywords: Biochemistry; Cancer.