Identification of long non-coding RNAs involved in leukemogenesis and venetoclax response in acute myeloid leukemia through functional CRISPR-dCas9 interference screens

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Cozzi, ElisabettaDepartment of Medicine, Karolinska Institute,Sören Lehmann (author)

Identification of long non-coding RNAs involved in leukemogenesis and venetoclax response in acute myeloid leukemia through functional CRISPR-dCas9 interference screens

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LIBRIS-ID:oai:DiVA.org:uu-469815
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-469815URI

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Language:English
Summary in:English

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The first three authors share authorship.The last two authors share authorship.
Acute myeloid leukemia (AML) is a malignant hematologic disease with poor prognosis. Increased understanding of disease biology is therefore needed to improve outcome for patients. While the protein-coding genome is well characterized in AML, knowledge about the involvement of non-coding genes is very limited in AML. Here, it was sought to investigate how long non-coding RNAs (lncRNAs) could contribute to disease biology and treatment resistance in AML. Three high-throughput lncRNA-CRISPR-interference screens were performed in MOLM-13 cells, knocking down about 8000 lncRNA expressed in hematopoietic cells. Effects on cell proliferation, cell differentiation and response to the anti-leukemic Bcl-2-inhibitor venetoclax were investigated upon lncRNA repression. LncRNAs most likely to positively or negatively regulate these processes were identified and top lncRNA candidates investigated with respect to expression in AML and healthy CD34+ cells and clinical AML correlations. Four lncRNAs involved in AML cell proliferation were identified (lncRNAs MIR17HG, CATG00000056335, CATG00000095269, CATG00000002239), two lncRNAs involved in differentiation (lncRNAs RP11-444A22.1, CATG00000058672) and seven lncRNAs implicated in venetoclax response. Among those, enhanced expression of proliferation-promoting lncRNA MIR17HG significantly correlated with poor outcome in AML patients (p= 0.03; p= 0.016). Further, lncRNA RP11-444A2 was identified as a predicted negative regulator of cell differentiation and was found to correlate with poor outcome (p=0.014). Further, lncRNA AC009299.3, predicted in venetoclax sensitivity, was found to be associated with poor outcome (p<0.0001), adverse risk (p=0.0014) and increased age (p=0.0045) in AML patients. Together, this study identified 14 lncRNAs proposed to be implicated in key leukemogenic events, highlighting their potential for elucidating AML biology, prognosis or treatment-response prediction and/or therapeutic use.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Hematologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Hematology hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Cancer och onkologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Cancer and Oncology hsv//eng
acute myeloid leukemia (AML)
long non-coding RNAs (lncRNAs)
CRISPR interference
proliferation
differentiation
venetoclax
prognosis
Molekylär medicin
Molecular Medicine

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Neddermeyer, AnneUppsala universitet,Institutionen för medicinska vetenskaper,Sören Lehmann(Swepub:uu)Annne270 (author)
Miliara, SophiaDepartment of Biosciences and Nutrition, Karolinska Institute,Andreas Lennartsson (author)
Lennartsson, AndreasDepartment of Biosciences and Nutrition, Karolinska Institute,Andreas Lennartsson (author)
Lehmann, SörenUppsala universitet,Institutionen för medicinska vetenskaper,Department of Medicine, Karolinska Institute, Huddinge, Sweden,Sören Lehmann(Swepub:uu)Sorle534 (author)
Department of Medicine, Karolinska InstituteSören Lehmann (creator_code:org_t)

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