Köhnke Thomas, Karigane Daiki, Hilgart Eleanor, Fan Amy C, Kayamori Kensuke, Miyauchi Masashi, Collins Cailin T, Suchy Fabian P, Rangavajhula Athreya, Feng Yang, Nakauchi Yusuke, Martinez-Montes Eduardo, Fowler Jonas L, Loh Kyle M, Nakauchi Hiromitsu, Koldobskiy Michael A, Feinberg Andrew P, Majeti Ravindra
Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University; Stanford, CA, 94305, USA.
Center for Epigenetics and Department of Medicine, Johns Hopkins University School of Medicine; Baltimore, MD, 21205, USA.
bioRxiv. 2024 Oct 29:2024.10.26.620318. doi: 10.1101/2024.10.26.620318.
Genetic mutations are being thoroughly mapped in human cancers, yet a fundamental question in cancer biology is whether such mutations are functionally required for cancer initiation, maintenance of established cancer, or both. Here, we study this question in the context of human acute myeloid leukemia (AML), where missense mutations often arise early, in pre-leukemic clonal hematopoiesis, and corrupt the DNA methylation landscape to initiate leukemia. We developed CRISPR-based methods to directly correct mutations in leukemic cells obtained from patients. Surprisingly, mutations were largely dispensable for disease maintenance. Replacing mutants with wild-type did not impair the ability of AML cells to engraft , and minimally altered DNA methylation. Taken together, mutations are initially necessary for AML initiation, but are largely dispensable for disease maintenance. The notion that initiating oncogenes differ from those that maintain cancer has important implications for cancer evolution and therapy.
基因突变正在人类癌症中被全面绘制图谱，但癌症生物学中的一个基本问题是，此类突变对于癌症的起始、已确立癌症的维持，或两者而言是否在功能上是必需的。在此，我们在人类急性髓系白血病（AML）的背景下研究这个问题，在AML中，错义突变常常在白血病前期克隆性造血过程中早期出现，并破坏DNA甲基化格局以引发白血病。我们开发了基于CRISPR的方法来直接纠正从患者获得的白血病细胞中的突变。令人惊讶的是，这些突变在很大程度上对于疾病维持是可有可无的。用野生型取代突变体并不损害AML细胞的植入能力，并且对DNA甲基化的改变极小。综上所述，这些突变对于AML起始最初是必需的，但在很大程度上对于疾病维持是可有可无的。起始癌基因与维持癌症的癌基因不同这一观点对癌症进化和治疗具有重要意义。
