LncRNAs exert important roles in myeloid differentiation and can respond to differentiation induction therapy. At present, two lncRNAs, HOTAIRM1 and NEAT1 are known to regulate the differentiation of AML cells. HOTAIRM1 is a myeloid-specific long non-coding transcript, which is transcribed from the locus between HOXA1 and HOXA2 genes. HOTAIRM1 regulates myeloid differentiation genes such as CD11b and CD18, and its knockdown impairs all-trans retinoic acid (ATRA)-induced granulocytic differentiation [
14]. This work could serve as a paradigm for exploring lncRNAs in AML, from the discovery of the lncRNA candidate to the investigation of the biological function. This work also has an interesting finding—HOTAIRM1 is derived from HOXA clusters, and in turn regulates the nearby genes in HOXA cluster. Whether this regulation is direct or indirect awaits further investigation. Another example is NEAT1, a widespread and abundant long noncoding RNA. Although myeloid differentiation is usually considered to be dominantly controlled by highly myeloid-specific factors, NEAT1 has been reported to be responsive to ATRA and be indispensable for ATRA-mediated myeloid differentiation [
28]. This observation indicates that myeloid differentiation also requires commonly expressed long noncoding transcripts. However, since both studies of HOTAIRM1 and NEAT1 mentioned above were conducted in myeloid leukemia cells, it has yet to be determined whether HOTAIRM1 and NEAT1 are required for normal myelopoiesis. Further in vivo studies are needed to evaluate their roles in normal hematopoiesis and the development of AML.
LncRNAs also exert effects on proliferation, cell cycle and apoptosis in AML cells. Such lncRNAs tend to be expressed more widely than those myeloid-specific transcripts that regulate differentiation. A typical example is lncRNA PVT1, which can promote the proliferation of AML cells [
21]. The oncogenic activity of PVT1 is closely related to MYC, whose overexpression can lead to hyper proliferation of cancer cells. A gain-of-function of both the MYC gene and the PVT1 lncRNA due to the amplification of 8q24.21 is observed in about 10% of AML patients [
30]. On the one hand, PVT1 protects MYC from degradation by direct physical interaction [
30]. On the other hand, PVT1 acts as a microRNA precursor for indirect regulation of MYC [
31]. The PVT1 locus can produce six annotated oncogenic microRNAs [
31,
32], and one of these microRNAs, hsa-miR-1204, which is derived from the exon 1b, has been reported to be able to enhance the expression level of MYC [
31]. From the example of PVT1, we should note that lncRNAs may have multifaceted roles and can function through multiple ways. Also, the co-amplification of PVT1 and MYC informs us that it might be interesting to see the association or causal relationship of copy number of lncRNAs with leukemogensis. In addition to PVT1, lncRNA UCA1 has also been reported to have the capability to modulate the proliferation of AML cells [
29]. UCA1 silencing by short-hairpin RNA transduction results in a significant reduction of cell proliferation, with an increase in the G1 phase and a decrease in the S phase. Another example is lncRNA CCAT1, which can coordinate the proliferation and differentiation of AML cells [
25]. Overexpression and knockdown experiments demonstrate that CCAT1 inhibits the PMA-induced monocytic differentiation as well as promotes the proliferation of AML-derived HL60 cells [
25]. As to apoptosis of AML cells, Xing et al. [
27] found that HOTAIR knockdown inhibits cell growth and colony formation, and also induces the apoptosis of AML cells [
27]. Of note, the oncogenic properties of these lncRNAs are not limited to leukemia, but can also be observed in solid tumors. For example, PVT1 can promote the proliferation of hepatocellular carcinoma and non-small cell lung cancer cells [
33,
34]. Similarly, CCAT1 can promote the proliferation and invasion of colon cancer cells, gallbladder cancer cells and hepatocellular carcinoma cells [
25,
35,
36]. These observations indicate that such lncRNAs usually share similar functions in leukemia and other types of malignancies. Further experiments are required to investigate the underlying mechanism by which these lncRNAs control the cellular phenotypes—proliferation, cell cycle and apoptosis in AML cells.
Recently, the discovery of a novel class of lncRNAs piques the curiosity of scientists and potentially ignites their efforts to characterize them: fusion transcripts between coding genes and lncRNAs. In an AML patient sample and an AML-derived HL-60 cell line, it is verified that NSMCE2 rearrangement gives rise to two novel chimeric genes, PVT1-NSMCE2 and CCDC26-NSMCE2 [
12]. Although their identities have been revealed, their involvement in leukemogenesis is elusive to date. It is likely that PVT1-NSMCE2 and CCDC26-NSMCE2 may contribute to the leukemogenesis through the oncogenic activity of PVT1 and CCDC26 [
26]. At present, our understanding of the fusion transcripts between lncRNAs and protein-coding genes is still in its infancy. Further experiments are required to determine the causal relationship between the protein-lncRNA-fusion transcripts and leukemia as well as the mechanism behind their behaviors.