Long non-coding RNAs in primary myelofibrosis: the dark matter in hematopoietic progenitor cells?

Primary myelofibrosis (PMF) is a hematological malignancy that belongs to a heterogeneous group of myeloproliferative neoplasms (MPNs). The three “classic” types of MPNs are polycythemia vera, essential thrombocythemia and PMF. Among them, PMF is the most aggressive, with a median survival of 5–7 years [1]. PMF is characterized by excessive fibrotic tissue formation in the bone marrow that is accompanied by significant clinical issues, such as splenomegaly, anemia and constitutional symptoms. It is thought to be caused by abnormalities in the hematopoietic stem and progenitor cells (HSCs) in the bone marrow.

In this issue of Leukemia and Lymphoma, Pennucci et al. [2] characterized the expression of three long non-coding RNAs (lncRNAs), WT1-as, MEG3 and ANRIL, in peripheral blood CD34 + cells from patients with PMF. This is a new and interesting topic of study in MPNs. The authors found significant up-regulation of WT1-as and MEG3, but not of ANRIL, in PMF samples when compared to healthy controls. Not a lot is known about the expression profile of WT1-as or Wilms’ tumor 1 antisense transcript. The only report linking WT1-as to cancer described defective splicing of WT1-as in acute myeloid leukemia (AML), suggesting that deregulation of this lncRNA may be involved in the development of this malignancy [3]. The protein-coding sense transcript WT1, on the other hand, was originally identified as a tumor suppressor gene, but accumulating evidence points to an oncogenic role in tumorigenesis [4]. WT1 is highly expressed in many solid tumors, as well as in AML and acute lymphoblastic leukemia (ALL), and is associated with disease progression in chronic myeloid leukemia (CML) and myelodysplastic syndrome (MDS) [4]. Given the positive correlation between WT1 and WT1-as expression described in the current article by Pennucci et al. [2], it seems that WT1-as may function as an oncogene in the development of human malignancies, including PMF. MEG3 or maternally expressed gene 3 has been found to function as a tumor suppressor lncRNA in a variety of human solid cancers, including brain, lung, renal, breast, cervix, colon and prostate cancer, as well as hematological malignancies, such as MDS, AML and multiple myeloma [5]. This is in contrast to the current article of Pennucci et al., where overexpression of MEG3 pointed to an oncogenic role of this lncRNA in PMF. However, several other genes, including some small non-coding microRNAs, have been found to function as a tumor suppressor in one type of cell or tissue and as an oncogene in other cell or tissue types, due to different targets and mechanisms of action. In addition, MEG3 is overexpressed in Wilms’ tumor, and can be increased or decreased in different hepatocellular carcinomas when compared to healthy liver tissues [5].

CD34 is a surface antigen that serves as a marker for identifying and separating HSCs, as it is not expressed on the surface of fully differentiated or mature hematopoietic cells [6]. Although selection of CD34 + cells from blood and bone marrow is the most common way of isolating HSCs, it has been suggested that CD34 − HSCs also exist [7]. Nevertheless, in general, human HSCs are identified as being predominantly CD34 + cell populations that also express CD59 and Thy1, that have low to no expression of CD38 and C-kit, while expression of lin is absent [8]. The number of CD34 + cells in the peripheral blood of patients with PMF is consistently higher than in healthy individuals (360-fold) or patients with other MPNs (18- to 30-fold), and these numbers increase significantly from patients with low-risk disease to patients with intermediate-risk and patients with high-risk disease [6]. Pennucci et al. [2] reported a trend toward more circulating CD34 + cells in patients who show concordant up-regulation of WT1 and WT1-as, and in patients with increased MEG3 expression. The fact that these patients with PMF were mainly distributed in high-risk categories is in agreement with previous reports that the number of CD34 + cells increases from low-risk to intermediate-risk and high-risk PMF [6], suggesting that concordant up-regulation of WT1 and WT1-as and/or increased MEG3 expression may be markers of high-risk disease.

Finally, lncRNAs are emerging as major players in stem cell biology. They can regulate pluripotency in embryonic stem cells and induced pluripotent stem cells, and are most likely also important for HSC self-renewal and differentiation [9]. Due to the deregulation of lncRNAs in cancer development and progression, and their involvement in major signaling pathways affected in cancer stem cells [9], it is very likely that lncRNAs may be important for the regulation of stem cell signaling in cancer cells, including HSCs. The data published by Pennucci and colleagues are important to further understand the complex world of lncRNAs.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.