An induced pluripotent stem cell t(7;12)(q36;p13) acute myeloid leukemia model shows high expression of MNX1 and a block in differentiation of the erythroid and megakaryocytic lineages. Issue 5 (3rd June 2022)

• Record Type: Journal Article
• Authors: Nilsson, Tina; Waraky, Ahmed; Östlund, Anders; Li, Susann; Staffas, Anna; Asp, Julia; Fogelstrand, Linda; Abrahamsson, Jonas; Palmqvist, Lars
• Is Part Of: International journal of cancer. Volume 151:Issue 5(2022)
• Page Start: 770
• Page End: 782
• Publication Date: 2022-06-03
• Subjects: AML -- chromosome translocation -- leukemia -- pluripotency -- stem cells; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.34122
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract: Acute myeloid leukemia (AML) results from aberrant hematopoietic processes and these changes are frequently initiated by chromosomal translocations. One particular subtype, AML with translocation t(7;12)(q36;p13), is found in children diagnosed before 2 years of age. The mechanisms for leukemogenesis induced by t(7;12) is not understood, in part because of the lack of efficient methods to reconstruct the leukemia‐associated genetic aberration with correct genomic architecture and regulatory elements. We therefore created induced pluripotent stem cell (iPSC) lines that carry the translocation t(7;12) using CRISPR/Cas9. These t(7;12) iPSC showed propensity to differentiate into all three germ layers, confirming retained stem cell properties. The potential for differentiation into hematopoietic stem and progenitor cells (HSPC) was shown by expression of CD34, CD43 and CD45. Compared with the parental iPSC line, a significant decrease in cells expressing CD235a and CD41a was seen in the t(7;12) iPSC‐derived HSPC (iHSPC), suggesting a block in differentiation. Moreover, colony formation assay showed an accumulation of cells at the erythroid and myeloid progenitor stages. Gene expression analysis revealed significant down‐regulation of genes associated with megakaryocyte differentiation and up‐regulation of genes associated with myeloid pathways but also genes typically seen in AML cases with t(7;12). Thus, this iPSC t(7;12) leukemia model of the t(7;12) AML subtype constitutes a valuable tool for further studies of the mechanisms for leukemia development and to find new treatment options. Abstract : What's new? Acute myeloid leukemia results from aberrant hematopoietic processes that are often initiated by chromosomal translocations. The mechanisms underlying leukemogenesis in pediatric patients with the t(7;12) translocation remain poorly understood. Here, the authors have created induced pluripotent stem cells (iPSC) with the t(7;12)(q36;p13) translocation using CRISPR/Cas9 technology. Characterization of these iPSC shows cell differentiation and growth properties as well as a gene expression signature similar to those seen in patients with t(7;12) acute myeloid leukemia. This model represents a valuable tool for further studies of the mechanisms behind the development of pediatric leukemia caused by this translocation.