Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine Berlin, Campus Virchow Clinic, Augustenburger Platz 1, 13353 Berlin, Germany.
Semin Cancer Biol. 2022 Sep;84:153-169. doi: 10.1016/j.semcancer.2021.03.034. Epub 2021 Apr 22.
Myeloid malignancies have always been at the forefront of an improved understanding of the molecular pathogenesis of cancer. In accordance, over the last years, basic research focusing on the aberrations underlying malignant transformation of myeloid cells has provided the basis for precision medicine approaches and subsequently has led to the development of powerful therapeutic strategies. In this review article, we will recapitulate what has happened since in the 1980s the use of all-trans retinoic acid (ATRA), as a first targeted cancer therapy, has changed one of the deadliest leukemia subtypes, acute promyelocytic leukemia (APL), into one that can be cured without classical chemotherapy today. Similarly, imatinib, the first molecularly designed cancer therapy, has revolutionized the management of chronic myeloid leukemia (CML). Thus, targeted treatment approaches have become the paradigm for myeloid malignancy, but many questions still remain unanswered, especially how identical mutations can be associated with different phenotypes. This might be linked to the impact of the cell of origin, gene-gene interactions, or the tumor microenvironment including the immune system. Continuous research in the field of myeloid neoplasia has started to unravel the molecular pathways that are not only crucial for initial treatment response, but also resistance of leukemia cells under therapy. Ongoing studies focusing on leukemia cell vulnerabilities do already point to novel (targetable) "Achilles heels" that can further improve myeloid cancer therapy.
髓系恶性肿瘤一直处于对癌症分子发病机制的理解的前沿。因此，在过去的几年中，专注于髓系细胞恶性转化异常的基础研究为精准医学方法提供了基础，并随后导致了强大治疗策略的发展。在这篇综述文章中，我们将回顾自 20 世纪 80 年代以来发生的情况，当时全反式维甲酸（ATRA）作为第一种靶向癌症治疗方法，已经将一种最致命的白血病亚型——急性早幼粒细胞白血病（APL）转变为今天无需经典化疗即可治愈的疾病。同样，伊马替尼作为第一种分子设计的癌症治疗方法，彻底改变了慢性髓系白血病（CML）的治疗管理。因此，靶向治疗方法已成为髓系恶性肿瘤的范例，但仍有许多问题尚未得到解答，尤其是相同的突变如何与不同的表型相关。这可能与起源细胞的影响、基因-基因相互作用或肿瘤微环境（包括免疫系统）有关。髓系肿瘤领域的持续研究已开始揭示不仅对初始治疗反应至关重要，而且对治疗下白血病细胞的耐药性也至关重要的分子途径。目前正在进行的专注于白血病细胞脆弱性的研究已经指出了新的（可靶向）“阿喀琉斯之踵”，这可以进一步改善髓系癌症治疗。
