Title
A genomics driven pluripotent stem cell model of infant acute lymphoblastic leukemia
Files
Publication Date
5-2023
Abstract
Acute lymphoblastic leukemia in infants (iALL) is a high-risk subtype of childhood leukemia, with poor survival outcomes despite intensive therapies. Rearrangement of KMT2A (KMT2A-r) on chromosome 11q23 is the most frequent cytogenetic abnormality in both iALL and pediatric acute myeloid leukemia (AML). Survival outcomes for children with KMT2A-r leukemia are generally very poor, despite intensive therapies, as KMT2A-r is associated with refractoriness to therapy and early relapse. KMT2A-r generates a driver fusion oncogene, most commonly KMT2A::AFF1 or KMT2A::MLLT1 in ALL, and KMT2A::MLLT3 in AML, resulting in epigenetic dysregulation of target gene transcription. iALL expressing MLL-AF4 is an unusual cancer in that other somatic mutations are uncommon and there are no known genetic risk factors. Our team has discovered rare pathogenic genomic variants in healthy blood cells from infants in remission from ALL. We detected germline variants in ERCC2 and MITF in multiple cases of MLL-AF4 ALL, and these were validated using external databases. We hypothesize that these and perhaps other rare, pathogenic variants detected in cancer predisposition genes impact the onset, severity, and response to therapies in KMT2A-r ALL. Unfortunately, research into this rare but devasting disease has been hindered by a lack of appropriate, representative models. This indicates an essential, outstanding need for the development of more representative model systems for KMT2A-r leukemias. Interestingly, iALL originates in utero with the most aggressive cases being associated with an early embryonic or fetal origin; however, little is known regarding how KMT2A-r subverts early hematopoiesis, the cell types of origin, or how it controls progression to leukemia.
In an effort to understand the role of newly discovered germline variants associated with iALL, we have created a highly controlled induced pluripotent stem (iPS) cell model system to understand the genomic and epigenetic landscape of iALL. Specifically, we engineered human iPS cell lines to express MLL-Af4 fusion and are employing CRISPR gene editing technology to introduce clinically identified variants of interest. Furthermore, we have used directed differentiation to produce functional human hematopoietic stem and progenitor (HSPCs) from iPS cells. Notably, this model recapitulates hematopoietic ontogeny. Our iPS cell-based iALL cell model system provides the opportunity to investigate a range of critical and outstanding questions of iALL disease initiation, progression, and treatment. Future studies include a comparison of this model to single cell transcriptomic datasets from pediatric leukemia patients from our Cancer Center Biorepository, and comparison with developmental datasets from human embryonic and fetal hematopoiesis.
Document Type
Poster
Recommended Citation
Nemechek, Jacqelyn; Draper, Julia; McDermott, Sarah; Pushel, Irina; Farooqi, Midhat S.; Guest, Erin M.; Perry, John M.; and Vivian, Jay L., "A genomics driven pluripotent stem cell model of infant acute lymphoblastic leukemia" (2023). Research at Children's Mercy Month 2023. 7.
https://scholarlyexchange.childrensmercy.org/research_month2023/7
Notes
Poster not submitted by Presenter.