Publication Date

9-2023

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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 iALL, occurring in 70% of cases. KMT2A-r is associated with chemotherapy resistance, early relapse, and rapid leukemic progression, all of which contribute to poor survival outcomes. The most common KMT2A-r in iALL is KMT2A::AFF1 (MLL::AF4), derived from t(4;11)(q21;23) and arises in utero as shown in multiple clinical studies. Infant ALL’s cell of origin is thought to be a very early hematopoietic precursor, with transcriptomic studies of iALL blasts showing similarities to hematopoietic stem and progenitor cells (HSPCs), multipotent progenitors and early lymphoid progenitors (ELPs). Despite this, much is unknown regarding how KMT2A::AFF1 transforms early hematopoiesis, the cell types of origin, or how it alters the severity of the disease. Additionally, existing iALL models fail to mimic human disease, which creates an essential, ongoing need for the development of representative model systems for this devastating disease. To understand the development and progression of iALL, we have created a highly controlled human induced pluripotent stem (iPS) cell model to uncover the genomic and epigenetic landscape and cellular evolution of KMT2A::AFF1 iALL. Preliminary studies reveal our ability to differentiate human iPS cells into functional HSPCs with multilineage differentiation capacity and successfully express the doxycycline inducible KMT2A::Aff1 transgene in a controlled manner. We have also generated an in-house reference library of single cell RNA sequencing data and have compared transcriptomes of KMT2A-r blasts from iALL patients. This data revealed KMT2A-r cells are transcriptionally similar to ELPs. The goal for future investigations is to use single cell genomics to investigate transcriptomic changes during hematopoietic differentiation of our KMT2A:Aff1 iPS cell line. We also plan to compare these cells to publicly available single cell RNA sequencing data from multiple datasets that encompass fetal bone marrow and HSPC development. Through this research we expect to discover unique mechanisms of iALL emergence and progression with the long-term goal to uncover targets specific to iALL for the development of new therapies.

Disciplines

Oncology | Pediatrics

Notes

Presented at Children's Oncology Group Fall 2023 Group Meeting; Atlanta, GA; September 5-8, 2023.

A Genomics Driven Pluripotent Stem Cell Model of Infant Acute Lymphoblastic Leukemia

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