Department of Clinical Science, University of Bergen, Bergen, Norway.
Department of Hematology, Jagiellonian University Medical College / University Hospital, Krakow, Poland.
Curr Med Chem. 2019;26(28):5262-5277. doi: 10.2174/0929867326666190325100636.
Myeloid neoplasms are a diverse group of malignant diseases with different entities and numerous patho-clinical features. They arise from mutated clones of hematopoietic stem- and progenitor cells which expand by outperforming their normal counterparts. The intracellular signaling profile of cancer cells is the sum of genetic, epigenetic and microenvironmental influences, and the multiple interconnections between different signaling pathways make pharmacological targeting complicated.
To present an overview of known somatic mutations in myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) and the inflammatory signaling pathways affected by them, as well as current efforts to therapeutically modulate this aberrant inflammatory signaling.
In this review, we extensively reviewed and compiled salient information with ClinicalTrials.gov as our source on ongoing studies, and PubMed as our authentic bibliographic source, using a focused review question.
Mutations affecting immune signal transduction are present to varying extents in clonal myeloid diseases. While MPN are dominated by a few common mutations, a multitude of different genes can be mutated in MDS and AML. Mutations can also occur in asymptomatic persons, a finding called clonal hematopoiesis of indeterminate potential (CHIP). Mutations in FLT3, JAK, STAT, CBL and RAS can lead to aberrant immune signaling. Protein kinase inhibitors are entering the clinic and are extensively investigated in clinical trials in MPN, MDS and AML.
In summary, this article summarizes recent research on aberrant inflammatory signaling in clonal myeloid diseases and the clinical therapeutic potential of modulation of signal transduction and effector proteins in the affected pathways.
髓系肿瘤是一组具有不同实体和众多病理临床特征的恶性疾病。它们起源于造血干细胞和祖细胞的突变克隆，这些克隆通过超越其正常对应物而扩增。癌细胞的细胞内信号谱是遗传、表观遗传和微环境影响的总和，不同信号通路之间的多种相互连接使得药物靶向复杂化。
介绍髓系增殖性肿瘤（MPN）、骨髓增生异常综合征（MDS）和急性髓系白血病（AML）中已知的体细胞突变以及受其影响的炎症信号通路，并介绍目前对这些异常炎症信号进行治疗性调节的努力。
在这篇综述中，我们广泛回顾并编译了使用 ClinicalTrials.gov 作为正在进行的研究的来源、使用 PubMed 作为我们真实的文献来源的相关信息，使用了一个重点审查问题。
影响免疫信号转导的突变在克隆性髓系疾病中存在不同程度的存在。虽然 MPN 主要由少数常见突变主导，但 MDS 和 AML 中可以发生多种不同的基因突变。突变也可以发生在无症状者中，这种情况称为不确定潜能的克隆性造血（CHIP）。FLT3、JAK、STAT、CBL 和 RAS 的突变可导致异常免疫信号。蛋白激酶抑制剂正在进入临床，并在 MPN、MDS 和 AML 的临床试验中得到广泛研究。
总之，本文总结了最近关于克隆性髓系疾病中异常炎症信号的研究，以及调节受影响通路中的信号转导和效应蛋白的临床治疗潜力。
