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

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 two 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 myeloid differentiation and megakaryocyte differentiation pathways. Compared with the parental iHSPC the t(7;12) iHSPC expressed high levels of MNX1, a characteristic strongly associated with pediatric AML with t(7;12). Thus, we have created an iPSC t(7;12) leukemia model that has strong similarities with the t(7;12) AML subtype and therefore constitutes a valuable tool for further studies of the mechanisms for leukemia development to find new treatment options.

ORGANISM(S): Homo sapiens

PROVIDER: GSE182168 | GEO | 2022/04/30

REPOSITORIES: GEO