Classic myeloproliferative neoplasms (cMPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are clonal disorders characterized by the overproduction of one kind or more of the blood cells. Somatic mutations are responsible for the clonal expansion of cells in cMPNs and more than 85 percent of the patients appear to have a mutation in one of the following three genes: JAK2, MPL, or CALR(1–3). Other somatic mutations, such as LNK, CBL, TET2, ASXL1, IDH, IKZF1, EZH2, or DNMT3A are also identified in some cMPN patients(4–7). Janus kinase 2 (commonly called JAK2) is a non-receptor tyrosine kinase(8). Mutation in exon 14 of JAK2 substitutes a bulky phenylalanine for a conserved valine at position 617 in the JH2 or pseudokinase domain (Val617Phe, V617F), which negatively regulates the kinase domain. The JAK2V617F mutation causes cytokine-independent activation of JAK-STAT pathway and accounts for hypersensitivity of hematopoietic progenitor cells in cMPNs to growth factors and other cytokines(9–11).
Mammalian genomes are pervasively transcribed to produce thousands of long non-coding RNAs (lncRNAs)(12, 13). LncRNAs are transcripts longer than 200 nucleotides that have little or no protein-coding capacity(14, 15). Nuclear lncRNAs can silence or activate gene expression in cis or in trans manner(16), guide DNA methylation and histone modification(17), interplay with nuclear domains(18), perform gene-control through sequestration(19) and regulate higher-order chromosomal interactions(20). Aberrant expression of many lncRNAs is involved in the progression of CML, a BCR-ABL-positive MPN. For example, in CML, lncRNA-BGL3 functions as a competitive endogenous RNA for binding microRNAs to cross-regulate phosphatase and tensin homolog (PTEN) expression, and Bcr-Abl-mediated cellular transformation critically requires silence of tumor-suppressor lncRNA-BGL3(21). Overexpression of lncRNA-H19 contributes to the progression of CML by enhancing cell survival, colony formation, and inhibiting cell apoptosis(22). LncRNA X-inactive specific transcript (Xist) is required for hematopoietic stem cell survival and function. Deleting Xist causes marrow fibrosis, leukemia, and histiocytic sarcoma(23). However, whether lncRNAs contribute to the pathogenesis and progression of BCR-ABL-negative cMPNs, especially JAK2V617F-positive cMPNs, remains to be explored. Hence, we undertook a comprehensive study examining lncRNA expression in JAK2V617F-positive cMPN patients and querying the functional consequences of lncRNA expression.
In this study, using lncRNA microarray analysis, we found that numerous lncRNAs are differentially expressed in JAK2V617F-positive cMPN patients compared to their JAK2V617F-negative counterparts. One of them, lncRNA RP11-432I5.4 (NCBI accession number HG508247), was identified to be greatly upregulated in JAK2V617F-positive MPN samples. Loss- or gain-of-function analysis indicated that lncRNA RP11-432I5.4 promoted tumorigenesis and progression, playing a vital role in JAK2V617F-positive cMPNs. This study demonstrated the mechanism of how lncRNA RP11-432I5.4 influences JAK2V617F-positive cMPNs and provides a potential strategy for the treatment of JAK2V617F-positive cMPNs.