| 1. |
- Cozzi, Elisabetta, et al.
(författare)
-
Identification of long non-coding RNAs involved in leukemogenesis and venetoclax response in acute myeloid leukemia through functional CRISPR-dCas9 interference screens
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- 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.
|
|
| 2. |
- Neddermeyer, Anne, et al.
(författare)
-
A new mutant NPM1/IDH2R140- and PML-RARA-associated lncRNA MALNC plays a role in AML biology, prognosis and drug response
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by poor prognosis that requires better understanding of its disease biology and new tools for suitable risk stratification and effective treatments. Long non-coding RNAs (lncRNAs) are involved in numerous molecular mechanisms, are implicated in tumor biology and can serve as clinical biomarkers, yet their role remains mostly unclear in AML. In this study, the aim was to discover and characterize lncRNAs implicated in AML and to describe their role in AML biology. Further aims were to explore their use as prognostic or predictive biomarkers. Using whole-transcriptome analysis, a novel lncRNA, here named MALNC, was identified. MALNC had elevated expression in two large AML cohorts compared to normal CD34+ cells. Clinical correlation analyses indicated that MALNC was almost uniquely expressed in patients with PML-RARA fusion gene and with co-mutated isocitrate dehydrogenase-2 R140 and nucleophosmin-1 (IDH2R140/NPM1). MALNC expression was specifically high at the promyelocytic stage and decreased with maturation in leukemic and normal cells. High MALNC expression associated independently with better overall survival. CRISPR-Cas9-knockout in promyelocytic cell lines impaired proliferation, colony formation and all-trans retinoic acid (ATRA)-induced differentiation. Also, MALNC-knockout dramatically sensitized cells to arsenic trioxide (ATO), ATO-ATRA combinatorial and Bcl-2-inhibitor venetoclax treatment as well as associated with cyclin-dependent kinase (Cdk)-inhibitor resistance. In conclusion, MALNC is overexpressed in certain subgroups of AML and could play a role during normal and leukemic hematopoietic maturation. Furthermore, it correlates with response to anti-leukemic drugs, which suggests a role as a predictive marker to drug response and survival in AML.
|
|
