Abstract—Acute myeloid leukemia (AML) is a genetically heterogeneous group of oncological diseases of the hematopoietic system, which are extremely difficult to treat. The development of new targeted drugs (Hylteritinib, Venetoclax) significantly improved the survival of patients, but resistance, as well as cytotoxic anti-leukemia drugs, often occurs. The search for new molecular targets for the development of effective approaches for the treatment of AML is very urgent. In blast cells of patients with AML, mutations, chromosomal rearrangements, and increased expression of a number of non-mutant genes, including transcription factor genes, are detected. The transcription factor Sp1 binds to GC-rich regions of regulatory regions of various genes and thus controls their expression. Sp1 targets include genes responsible for proliferation, cell cycle regulation, and differentiation. In many malignant diseases, a high level of Sp1 gene expression is associated with an unfavorable prognosis, therefore, Sp1 is considered as a promising therapeutic target for cancer. In this paper, we estimated the expression levels of Sp1 in various malignant tissues. Increased Sp1 expression was detected in samples obtained from patients with AML, acute lymphoblastic leukemia, Ewing sarcoma, ovarian and kidney cancer. It is also shown that Sp1 expression correlates with the expression of genes encoding cytokine receptors and growth factors (CSF1R and IL6R), intracellular kinases (CSK, SYK, PAK1, ILK, JAK2), and transcription factor LMO2. The correlation between expression levels of Sp1 and CSF1R, SYK, Jak2 and LMO2 is also characteristic of transplanted human leukemia cells. We measured expression levels of Sp1, CSF1R, ILK, PAK1 in the cells of three transplantable lines of human leukemia and found increased levels of expression of these genes in Kasumi-1 cells. In addition, we showed that Kasumi-1 cells are most sensitive to Mitramycin, a drug that displaces Sp1 from its targets with DNA. Our data indicate the need to identify AML cells that are most sensitive to inhibition of Sp1 activity in order to assess the possibility of suppressing its activity in vivo.

中文翻译：

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SP1，CSF1R和PAK1的高表达水平与白血病细胞对抗生素光神霉素的敏感性相关

摘要—急性髓细胞性白血病（AML）是造血系统肿瘤疾病的遗传异质性群体，很难治愈。新的靶向药物（Hylteritinib，Venetoclax）的开发显着改善了患者的存活率，但耐药性以及细胞毒性抗白血病药物经常发生。寻找新的分子靶标以开发治疗AML的有效方法非常迫切。在患有AML的患者的胚细胞中，检测到突变，染色体重排以及许多非突变基因（包括转录因子基因）的表达增加。转录因子Sp1与各种基因调节区的富含GC的区域结合，从而控制它们的表达。Sp1靶标包括负责增殖的基因，细胞周期调节和分化。在许多恶性疾病中，Sp1基因表达与预后不良有关，因此，Sp1被认为是有希望的癌症治疗靶标。在本文中，我们估计了Sp1在各种恶性组织中的表达水平。从AML，急性淋巴细胞白血病，尤因肉瘤，卵巢癌和肾癌患者的样本中检测到Sp1表达增加。还显示Sp1表达与编码细胞因子受体和生长因子（CSF1R和IL6R），细胞内激酶（CSK，SYK，PAK1，ILK，JAK2）和转录因子LMO2的基因的表达相关。Sp1的表达水平与CSF1R，SYK，Jak2和LMO2也是移植的人类白血病细胞的特征。我们测量了三种可移植人白血病细胞系中Sp1，CSF1R，ILK，PAK1的表达水平，发现这些基因在Kasumi-1细胞中的表达水平增加。此外，我们证明了Kasumi-1细胞对Mitramycin最敏感，Mitramycin是一种用DNA取代Sp1靶标的药物。我们的数据表明需要鉴定对Sp1活性抑制最敏感的AML细胞，以评估在体内抑制其活性的可能性。