Dong CY, Liu XY, Wang N, Wang LN, Yang BX, Ren Q, Liang HY, Ma XT

Dong CY, Liu XY, Wang N, Wang LN, Yang BX, Ren Q, Liang HY, Ma XT. and associated with poor prognosis, is identified as a TWIST-1 coexpressed gene in myeloid leukemia patients and partially contributes to TWIST-1-mediated leukemogenic effects. Moreover, patients with higher TWIST-1 expression have shorter overall and event-free survival (OS and EFS) in AML. Multivariate analysis further demonstrates that TWIST-1 overexpression is a novel independent unfavourable predictor for both OS and EFS in AML. These data highlight TWIST-1 as a new candidate gene contributing to leukemogenesis of myeloid leukemia, and propose possible new avenues for improving risk and treatment stratification in AML. and vertebrates [7C9]. In human, overexpression of TWIST-1 has been TSPAN6 observed in various solid tumors and is often associated with aggressive phenotypes and poor prognosis [10C14]. It’s now well accepted that TWIST-1, which may function as a multifunctional proto-oncogene during tumorigenesis and progression of solid tumors, protects cells from chemotherapy-induced apoptosis and senescence and promotes tumor epithelial-mesenchymal transition [13, 15C19]. In many cancers, evidence suggests that a small subset of malignant cells, termed cancer stem cells (CSCs), is wholly responsible for tumor propagation, metastasis, disease relapse and drug resistance. Targeting of CSCs carries the hope of curing cancer [20]. Recently, TWIST-1 has attracted intense interest due to its contribution in generation and maintenance of CSCs. Overexpression of TWIST-1 in breast cell lines, head and neck squamous cell carcinoma cells, and cervical cancer cells enhanced tumor-initiating FX1 and self-renewal capability [21C23]. In the blood system, our previous study demonstrates that TWIST-1 is highly expressed in mouse long-term hematopoietic FX1 stem cells (LT-HSCs) and is a novel regulator of HSC self-renewal and myeloid lineage development [24]. Thus far, there are only a few studies concerning the role of TWIST-1 in human hematopoietic malignancies. Cosset et al reveals that overexpression of TWIST-1 represents a prognostic factor in CML and may contribute to drug resistance [25]. TWIST-1 has also been reported as an antiapoptotic factor in myelodysplastic syndromes (MDS) [26]. However, the role of TWIST-1 in AML and acute lymphoid leukemia (ALL), whether it is associated with leukemia stem cells (LSCs), and its potential pathogenic mechanism in CML remain unknown. We first determined TWIST-1 expression level by quantitative real-time FX1 PCR and immunohistochemical (IHC) in different hematopoietic malignancies including AML, ALL and CML. Our study demonstrated that TWIST-1 was highly expressed in bone marrow mononuclear cells (BMMNCs) of patients with AML and CML, whereas normalization of TWIST-1 expression was observed in patients with ALL. We also found that TWIST-1 enhanced cell growth, colony formation, drug resistance and tumor formation in AML and CML cell lines. In addition, we analyzed TWIST-1 expression patterns in different hematopoietic cell populations from AML and CML patients, FX1 and found that TWIST-1 was most highly expressed in CD34+CD38? cells but showed a low abundance in more differentiated descendants. TWIST-1 knockdown impaired stem/progenitor cell colony-forming capability of principal myeloid leukemia Compact disc34+ cells. Furthermore, TWIST-1 could mediate the appearance of c-MPL by interfering with RUNX1. Overexpression of c-MPL could considerably attenuate the inhibitory ramifications of knockdown TWIST-1 over the development of AML and CML cell lines. TWIST-1 overexpression led to the activation of phosphorylation from the JAK2/ERK and PI3K/AKT pathways that are downstream pathways of c-MPL. These total results suggested an operating interaction between TWIST-1 and c-MPL in AML and CML cell lines. Most of all, we discovered TWIST-1 being a book independent prognostic aspect for poor final result in AML. Outcomes Overexpression of TWIST-1 in myeloid leukemia cell lines and sufferers with AML and CML To look for the potential function of TWIST-1 in leukemia, we quantified the protein and mRNA appearance of TWIST-1 in the myeloid cell lines NB4, KG1a, J6C1, U937, HL-60, and K562, produced from sufferers with myeloid leukemia originally, aswell as CEM, Ramos, Jurkat, and Namalwa produced from leukemia of lymphoid origins, or.