IWASAKI Masayuki
   Department   Research Institutes and Facilities, Research Institutes and Facilities
   Position   Assistant Professor
Article types Original article
Language English
Peer review Peer reviewed
Title MLL leukemia induction by t(9;11) chromosomal translocation in human hematopoietic stem cells using genome editing.
Journal Formal name：Blood advances
Abbreviation：Blood Adv
ISSN code：24739537/24739529
Domestic / ForeginForegin
Volume, Issue, Page 2(8),pp.832-845
Author and coauthor Schneidawind Corina, Jeong Johan, Schneidawind Dominik, Kim In-Suk, Duque-Afonso Jesús, Wong Stephen Hon Kit, Iwasaki Masayuki, Breese Erin H, Zehnder James L, Porteus Matthew, Cleary Michael L
Publication date 2018/04
Summary Genome editing provides a potential approach to model de novo leukemogenesis in primary human hematopoietic stem and progenitor cells (HSPCs) through induction of chromosomal translocations by targeted DNA double-strand breaks. However, very low efficiency of translocations and lack of markers for translocated cells serve as barriers to their characterization and model development. Here, we used transcription activator-like effector nucleases to generate t(9;11) chromosomal translocations encoding MLL-AF9 and reciprocal AF9-MLL fusion products in CD34+ human cord blood cells. Selected cytokine combinations enabled monoclonal outgrowth and immortalization of initially rare translocated cells, which were distinguished by elevated MLL target gene expression, high surface CD9 expression, and increased colony-forming ability. Subsequent transplantation into immune-compromised mice induced myeloid leukemias within 48 weeks, whose pathologic and molecular features extensively overlap with de novo patient MLL-rearranged leukemias. No secondary pathogenic mutations were revealed by targeted exome sequencing and whole genome RNA-sequencing analyses, suggesting the genetic sufficiency of t(9;11) translocation for leukemia development from human HSPCs. Thus, genome editing enables modeling of human acute MLL-rearranged leukemia in vivo, reflecting the genetic simplicity of this disease, and provides an experimental platform for biological and disease-modeling applications.
DOI 10.1182/bloodadvances.2017013748
PMID 29650777