Department of Biochemistry, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad, TS, 500046, India.
Cancer Immunol Immunother. 2021 Dec;70(12):3477-3488. doi: 10.1007/s00262-021-02937-0. Epub 2021 Apr 23.
Acute megakaryocytic leukemia (AMKL) is one of the rarest sub-types of acute myeloid leukemia (AML). AMKL is characterized by high proliferation of megakaryoblasts and myelofibrosis of bone marrow, this disease is also associated with poor prognosis. Previous analyses have reported that the human megakaryoblastic cells can be differentiated into cells with megakaryocyte (MK)-like characteristics by phorbol 12-myristate 13-acetate (PMA). However, little is known about the mechanism responsible for regulating this differentiation process. We performed long non-coding RNA (lncRNA) profiling to investigate the differently expressed lncRNAs in megakaryocyte blast cells treated with and without PMA and examined those that may be responsible for the PMA-induced differentiation of megakaryoblasts into MKs. We found 30 out of 90 lncRNA signatures to be differentially expressed after PMA treatment of megakaryoblast cells, including the highly expressed JPX lncRNA. Further, in silico lncRNA-miRNA and miRNA-mRNA interaction analysis revealed that the JPX is likely involved in unblocking the expression of TGF-β receptor (TGF-βR) by sponging oncogenic miRNAs (miR-9-5p, miR-17-5p, and miR-106-5p) during MK differentiation. Further, we report the activation of TGF-βR-induced non-canonical ERK1/2 and PI3K/AKT pathways during PMA-induced MK differentiation and ploidy development. The present study demonstrates that TGF-βR-induced non-canonical ERK1/2 and PI3K/AKT pathways are associated with PMA-induced MK differentiation and ploidy development; in this molecular mechanism, JPX lncRNA could act as a decoy for miR-9-5p, miR-17-5p, and miR-106-5p, titrating them away from TGF-βR mRNAs. Importantly, this study reveals the activation of ERK1/2 and PI3K/AKT pathway in PMA-induced Dami cell differentiation into MK. The identified differentially expressed lncRNA signatures may facilitate further study of the detailed molecular mechanisms associated with MK development. Thus, our data provide numerous targets with therapeutic potential for the modulation of the differentiation of megakaryoblastic cells in AMKL.
急性巨核细胞白血病（AMKL）是急性髓细胞白血病（AML）中最罕见的亚型之一。AMKL 的特征是巨核母细胞的高度增殖和骨髓纤维化，这种疾病也与预后不良有关。以前的分析报告称，人巨核母细胞可以通过佛波醇 12-肉豆蔻酸 13-乙酸酯（PMA）分化为具有巨核细胞（MK）样特征的细胞。然而，对于调节这种分化过程的机制知之甚少。我们进行了长非编码 RNA（lncRNA）谱分析，以研究用和未用 PMA 处理的巨核母细胞中的差异表达 lncRNA，并检查那些可能负责 PMA 诱导巨核母细胞向 MK 分化的 lncRNA。我们发现，在 PMA 处理巨核母细胞后，90 个 lncRNA 特征中有 30 个表达差异，包括高度表达的 JPX lncRNA。此外，在 lncRNA-miRNA 和 miRNA-mRNA 相互作用的计算机分析中，JPX 可能通过海绵吸附致癌 miRNA（miR-9-5p、miR-17-5p 和 miR-106-5p）来解除 TGF-β 受体（TGF-βR）的表达，从而参与 MK 分化。此外，我们报告了在 PMA 诱导的 MK 分化和倍性发育过程中 TGF-βR 诱导的非经典 ERK1/2 和 PI3K/AKT 途径的激活。本研究表明，TGF-βR 诱导的非经典 ERK1/2 和 PI3K/AKT 途径与 PMA 诱导的 MK 分化和倍性发育有关；在这种分子机制中，JPX lncRNA 可以作为 miR-9-5p、miR-17-5p 和 miR-106-5p 的诱饵，将它们从 TGF-βR mRNA 中滴定出来。重要的是，这项研究揭示了 ERK1/2 和 PI3K/AKT 途径在 PMA 诱导的 Dami 细胞向 MK 分化中的激活。鉴定的差异表达 lncRNA 特征可能有助于进一步研究与 MK 发育相关的详细分子机制。因此，我们的数据为调节 AMKL 中的巨核母细胞分化提供了许多具有治疗潜力的靶点。
