Vagapova E R, Lebedev T D, Tikhonova A D, Goikhman B V, Ivanenko K A, Spirin P V, Prassolov V S
Engelhardt Institute of Molecular Biology Russian Academy of Sciences, Moscow, 119991 Russia.
Mol Biol (Mosk). 2020 May-Jun;54(3):522-528. doi: 10.31857/S0026898420030192.
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 Sp 1 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.
急性髓系白血病（AML）是造血系统的一组具有遗传异质性的肿瘤性疾病，极难治疗。新型靶向药物（海乐替尼、维奈托克）的研发显著提高了患者的生存率，但耐药性以及细胞毒性抗白血病药物的耐药情况仍经常出现。寻找用于开发有效治疗AML方法的新分子靶点迫在眉睫。在AML患者的原始细胞中，可检测到突变、染色体重排以及包括转录因子基因在内的一些非突变基因的表达增加。转录因子Sp1与各种基因调控区域富含GC的区域结合，从而控制它们的表达。Sp1的靶点包括负责增殖、细胞周期调控和分化的基因。在许多恶性疾病中，Sp1基因的高表达与不良预后相关，因此，Sp1被认为是一种有前景的癌症治疗靶点。在本文中，我们评估了Sp1在各种恶性组织中的表达水平。在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。研究还表明，Sp1表达与编码细胞因子受体和生长因子（CSF1R和IL-6R）、细胞内激酶（CSK、SYK、PAK1、ILK、JAK2）以及转录因子LMO2的基因表达相关。Sp1与CSF1R、SYK、Jak2和LMO2表达水平之间的相关性在移植的人白血病细胞中也很明显。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细胞中的表达水平升高。此外，我们表明Kasumi-1细胞对丝裂霉素最敏感，丝裂霉素是一种能将Sp1从其与DNA的靶点上置换下来的药物。我们的数据表明，有必要识别对抑制Sp1活性最敏感的AML细胞，以评估在体内抑制其活性的可能性。
