Expression and functional relevance of long non-coding RNAs in acute myeloid leukemia stem cells

Bill, Marius; Papaioannou, Dimitrios; Karunasiri, Malith; Kohlschmidt, Jessica; Pepe, Felice; Walker, Christopher J.; Walker, Allison R.; Brannan, Zachary; Pathmanathan, Aparna; Zhang, Xiaoli; Mrózek, Krzysztof; LaRocco, Allison; Volinia, Stefano; Bloomfield, Clara D.; Garzon, Ramiro; Dorrance, Adrienne M.

doi:10.1038/s41375-019-0429-5

Cited by 55 publications

(40 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The expression profile of lncRNAs is associated with clinical features and outcome in AML patients (Garzon et al, 2014). In two RNA-seq datasets reported recently, DANCR was identified to be correlated strongly with features of leukemia stem cells, a subgroup of cells showing increased chemotherapy resistance (Bill et al, 2019).…”

Section: Disscussionmentioning

confidence: 99%

Long noncoding RNA DANCR confers cytarabine resistance in acute myeloid leukemia by activating autophagy via the miR‐874‐3P/ATG16L1 axis

et al. 2021

View full text Add to dashboard Cite

Long noncoding RNA DANCR confers cytarabine resistance in acute myeloid leukemia by activating autophagy via the miR-874-3P/ATG16L1 axis AbstractAutophagy is an important mechanism involved in the regulation of acute myeloid leukemia (AML) chemoresistance. The long noncoding RNA (lncRNA) DANCR exhibits oncogenic activity in several types of human cancers, including AML, but it remains unclear whether it regulates autophagy and chemoresistance in AML. We report here that cytarabine (Ara-C) treatment elevates DANCR expression in human AML cells. In addition, DANCR overexpression confers and its knockdown diminishes Ara-C resistance in human AML cells, suggesting that DANCR positively regulates AML chemoresistance to Ara-C. Moreover, DANCR promotes autophagy in Ara-C-treated human AML cells and acts as a sponge to decrease miR-20a-5p expression, thereby upregulating the expression of ATG16L1, a critical component of the autophagy machinery. Importantly, ATG16L1 silencing abrogates DANCR-promoted autophagy and markedly restores DANCR-conferred Ara-C resistance, suggesting that DANCR promotes MIR-874-3P/ATG16L1 axis-regulated autophagy to confer Ara-C resistance in human AML cells. Together, this study identifies DANCR as a positive regulator of Ara-C resistance in human AML cells, suggesting this lncRNA as a potential target for overcoming Ara-C resistance in AML chemotherapy.

show abstract

Section: Disscussionmentioning

confidence: 99%

Long noncoding RNA DANCR confers cytarabine resistance in acute myeloid leukemia by activating autophagy via the miR‐874‐3P/ATG16L1 axis

et al. 2021

View full text Add to dashboard Cite

show abstract

“…H19 lncRNA is pivotal for the development of embryonic hematopoietic stem cells [17]. LncRNA DANCR is upregulated in leukemia stem cells (LSCs), and its knockdown results in the decreased self-renewal of LSCs [25]. However, whether lncRNAs could specifically play regulatory roles in the balance between self-renewal and differentiation in MLL leukemia or serve as effector molecules of DOT1L to affect the abnormal activation of HOXA genes has not been reported yet.…”

Section: Introductionmentioning

confidence: 99%

The lncRNA LAMP5-AS1 drives leukemia cell stemness by directly modulating DOT1L methyltransferase activity in MLL leukemia

et al. 2020

View full text Add to dashboard Cite

Background: Mixed-lineage leukemia (MLL) gene rearrangements trigger aberrant epigenetic modification and gene expression in hematopoietic stem and progenitor cells, which generates one of the most aggressive subtypes of leukemia with an apex self-renewal. It remains a challenge to directly inhibit rearranged MLL itself because of its multiple fusion partners and the poorly annotated downstream genes of MLL fusion proteins; therefore, novel therapeutic targets are urgently needed. Methods: qRT-PCR, receiver operating characteristic (ROC), and leukemia-free survival analysis were used to validate LAMP5-AS1 (LAMP5 antisense 1) expression and evaluate its clinical value. We performed in vitro and in vivo experiments to investigate the functional relevance of LAMP5-AS1 in MLL leukemia progression and leukemia cell stemness. RNA electrophoretic mobility shift assays (EMSA), histone methyltransferase assay, RNA pull-down assay, and RNA fluorescence in situ hybridization (FISH) were used to validate the relationship between LAMP5-AS1 and the methyltransferase activity of DOT1L. The downstream ectopic target genes of LAMP5-AS1/DOT1L were validated by the chromatin immunoprecipitation (ChIP) and western blot. Results: We discovered that a long noncoding RNA (lncRNA) LAMP5-AS1 can promote higher degrees of H3K79 methylation, followed by upregulated expression of the self-renewal genes in the HOXA cluster, which are responsible for leukemia stemness in context of MLL rearrangements. We found that LAMP5-AS1 is specifically overexpressed in MLL leukemia patients (n = 58) than that in the MLL-wt leukemia (n = 163) (p < 0.001), and the patients with a higher expression level of LAMP5-AS1 exhibited a reduced 5-year leukemia-free survival (p < 0.01). LAMP5-AS1 suppression significantly reduced colony formation and increased differentiation of primary MLL leukemia CD34+ cells. Mechanistically, LAMP5-AS1 facilitated the methyltransferase activity of DOT1L by directly binding its Lys-rich region of catalytic domain, thus promoting the global patterns of H3K79 dimethylation and trimethylation in cells. These observations supported that LAMP5-AS1 upregulated H3K79me2/me3 and the

show abstract

“…The DANCR gene is bound by MYC when MYC is induced in the P493-6 cells in a time-dependent manner which is consistent with the findings of Hart et al ( 73 ) and other studies that followed DANCR expression in several tumors ( 82 – 89 ). Of interest here is the finding that DANCR plays a role in Acute Myeloid Leukemia (AML) ( 90 ). AML is a heterogeneous leukemia with a hierarchical cellular organization, driven by a population of so-called leukemia stem cells (LSCs) that have an abnormally robust self-renewal capacity and increased chemotherapy resistance.…”

Section: Myc Regulated Lncrnasmentioning

confidence: 99%

“…AML is a heterogeneous leukemia with a hierarchical cellular organization, driven by a population of so-called leukemia stem cells (LSCs) that have an abnormally robust self-renewal capacity and increased chemotherapy resistance. RNA-seq on cytogenetically normal AML patients (CN-AML, i.e., lacking chromosomal aberrations) demonstrated that DANCR was specifically expressed in LSCs and the knockdown of DANCR resulted in the downregulation of MYC expression ( 90 ). These observations and the finding that disrupting DANCR in a murine AML mouse model prolonged the survival of the animals after serial transplantation owing to a lower self-renewal capacity and dormancy of leukemic cells made a strong case for an important functional role of this lncRNA in the maintenance or progression of AML ( 90 ).…”

Section: Myc Regulated Lncrnasmentioning

confidence: 99%

“…RNA-seq on cytogenetically normal AML patients (CN-AML, i.e., lacking chromosomal aberrations) demonstrated that DANCR was specifically expressed in LSCs and the knockdown of DANCR resulted in the downregulation of MYC expression ( 90 ). These observations and the finding that disrupting DANCR in a murine AML mouse model prolonged the survival of the animals after serial transplantation owing to a lower self-renewal capacity and dormancy of leukemic cells made a strong case for an important functional role of this lncRNA in the maintenance or progression of AML ( 90 ). The features of DANCR in hematological malignancies makes this lncRNA a good candidate for a potential therapeutical application.…”

Section: Myc Regulated Lncrnasmentioning

confidence: 99%

See 1 more Smart Citation

Crosstalk Between MYC and lncRNAs in Hematological Malignancies

Arman

Möröy

2020

Front. Oncol.

View full text Add to dashboard Cite

The human genome project revealed the existence of many thousands of long non-coding RNAs (lncRNAs). These transcripts that are over 200 nucleotides long were soon recognized for their importance in regulating gene expression. However, their poor conservation among species and their still controversial annotation has limited their study to some extent. Moreover, a generally lower expression of lncRNAs as compared to protein coding genes and their enigmatic biochemical mechanisms have impeded progress in the understanding of their biological roles. It is, however, known that lncRNAs engage in various kinds of interactions and can form complexes with other RNAs, with genomic DNA or proteins rendering their functional regulatory network quite complex. It has emerged from recent studies that lncRNAs exert important roles in gene expression that affect many cellular processes underlying development, cellular differentiation, but also the pathogenesis of blood cancers like leukemia and lymphoma. A number of lncRNAs have been found to be regulated by several well-known transcription factors including Myelocytomatosis viral oncogene homolog ( MYC ). The c-MYC gene is known to be one of the most frequently deregulated oncogenes and a driver for many human cancers. The c- MYC gene is very frequently activated by chromosomal translocations in hematopoietic cancers most prominently in B- or T-cell lymphoma or leukemia and much is already known about its role as a DNA binding transcriptional regulator. Although the understanding of MYC’s regulatory role controlling lncRNA expression and how MYC itself is controlled by lncRNA in blood cancers is still at the beginning, an intriguing picture emerges indicating that c-MYC may execute part of its oncogenic function through lncRNAs. Several studies have identified lncRNAs regulating c- MYC expression and c-MYC regulated lncRNAs in different blood cancers and have unveiled new mechanisms how these RNA molecules act. In this review, we give an overview of lncRNAs that have been recognized as critical in the context of activated c-MYC in leukemia and lymphoma, describe their mechanism of action and their effect on transcriptional reprogramming in cancer cells. Finally, we discuss possible ways how an interference with their molecular function could be exploited for new cancer therapies.

show abstract

Expression and functional relevance of long non-coding RNAs in acute myeloid leukemia stem cells

Cited by 55 publications

References 42 publications

Long noncoding RNA DANCR confers cytarabine resistance in acute myeloid leukemia by activating autophagy via the miR‐874‐3P/ATG16L1 axis

Long noncoding RNA DANCR confers cytarabine resistance in acute myeloid leukemia by activating autophagy via the miR‐874‐3P/ATG16L1 axis

The lncRNA LAMP5-AS1 drives leukemia cell stemness by directly modulating DOT1L methyltransferase activity in MLL leukemia

Crosstalk Between MYC and lncRNAs in Hematological Malignancies

Contact Info

Product

Resources

About