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Myeloid Leukemia Vulnerabilities Embedded in Long Noncoding RNA Locus

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 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, perturbation caused strong and selective impairment of leukemia cells of various genetic backgrounds over normal hematopoietic stem and progenitor cells , and depletion of patient-derived xenografts .

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References
1.
Alejo-Valle O, Weigert K, Bhayadia R, Ng M, Issa H, Beyer C . The megakaryocytic transcription factor ARID3A suppresses leukemia pathogenesis. Blood. 2021; 139(5):651-665. PMC: 9632760. DOI: 10.1182/blood.2021012231. View

2.
Milne T, Kim J, Wang G, Stadler S, Basrur V, Whitcomb S . Multiple interactions recruit MLL1 and MLL1 fusion proteins to the HOXA9 locus in leukemogenesis. Mol Cell. 2010; 38(6):853-63. PMC: 2902588. DOI: 10.1016/j.molcel.2010.05.011. View

3.
Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View

4.
Heckl D, Kowalczyk M, Yudovich D, Belizaire R, Puram R, McConkey M . Generation of mouse models of myeloid malignancy with combinatorial genetic lesions using CRISPR-Cas9 genome editing. Nat Biotechnol. 2014; 32(9):941-6. PMC: 4160386. DOI: 10.1038/nbt.2951. View

5.
Chen C, Yu W, Tober J, Gao P, He B, Lee K . Spatial Genome Re-organization between Fetal and Adult Hematopoietic Stem Cells. Cell Rep. 2019; 29(12):4200-4211.e7. PMC: 7262670. DOI: 10.1016/j.celrep.2019.11.065. View