Sequential CRISPR gene editing in human iPSCs charts the clonal evolution of myeloid leukemia and identifies early disease targets

From development toward therapeutics, a collaborative effort on blood progenitors

“…The above findings included optimization of hPSC lines and directed differentiation of hPSCs into desired lineages, as well as modeling hematopoietic disorders using patient-derived iPSCs. Along with the findings presented at this meeting, multiple efforts have been made to acquire naive hPSCs (Chang et al, 2021;Giulitti et al, 2019), and patient-derived iPSCs have been created to model many hematologic disorders such as MDS and other myeloid leukemias (Chao et al, 2017;Wang et al, 2021;Wesely et al, 2020). These approaches will allow us to model and discover human biology and provide valuable insights for potential translational therapies in human cells and patients.…”

Clonal hematopoiesis and associated diseases: A review of recent findings

“…A recent report showed that aging increases the frequency of CD61‐high myeloid‐biased LT‐HSCs that further promote a myeloid output in response to inflammatory stimuli. 53 In addition, a CRISPR‐Cas9–mediated sequential KI developed in human cells showed that mutations in ASXL1 , SRSF2 , and NRAS activated the innate immunity signaling 54 pathways. Therefore, a combination of aging and CHIP‐associated mutations might activate inflammation by increasing the production of inflammatory cytokines.…”

“…Recently, a report showed that blocking signaling pathways in innate immunity with the help of agents, such as IRAK1/4 inhibitors, had prophylaxis effects on leukemogenesis. 54 In addition, age‐associated changes in the bone marrow microenvironment could serve as promising therapeutic targets for treating CHIP. Upregulation of TGFβ and IL‐6 signaling has been observed 81 in aged bone marrow stroma.…”

“…As mentioned above, activation of the signaling pathways in innate immunity would confer a competitive advantage to HSCs with CHIP‐associated mutations. Recently, a report showed that blocking signaling pathways in innate immunity with the help of agents, such as IRAK1/4 inhibitors, had prophylaxis effects on leukemogenesis 54 . In addition, age‐associated changes in the bone marrow microenvironment could serve as promising therapeutic targets for treating CHIP.…”

The high-performance technology CRISPR/Cas9 improves knowledge and management of acute myeloid leukemia

“…An early and persistent event in the process of leukemogenesis was a dysregulation of inflammatory signaling, which was cell-autonomous. It could serve as a therapeutic target 7 . Using CRISPR/Cas9 system it has been established that loss of the FBXO11 protein, which is part of the SCF ubiquitin ligase complex, produces cytokine independent growth of MDS-L cells.…”