Publication Date

9-2024

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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) occurs in 70% of cases and 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). This KMT2A-r generates a driver fusion oncogene which leads to epigenetic dysregulation of target gene transcription. 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). Unfortunately, research into this devastating disease has been hampered by the lack of a representative model of iALL Attempts at creation of an iALL models have led to a variety of results including myeloid neoplasms, lymphomas, myeloid/lymphoid hyperplasia or leukemia, mature B cell neoplasias, or in one instance, a B-lymphoblastic leukemia with prolonged latency. Because of these failures, much remains unknown regarding how KMT2A::AFF1 transforms early hematopoiesis or how it alters the severity of the disease. To understand the developmental state of the cell of origin and progression of iALL, we have created a highly controlled human inducible pluripotent stem (iPS) cell model of KMT2A::AFF1 iALL. Specifically, we engineered human iPS cell lines with doxycycline regulatable expression of KMT2A::AFF1 fusion and have confirmed expression of the KMT2A::AFF1 transcript. Through directed differentiation we have also produced functional HSPCs from iPS cells with multilineage differentiation capacity, as evidenced by differentiated cells being transcriptionally similar to erythrocytes, megakaryocytes, and monocytes. The iPS cells are currently being guided through lymphocyte differentiation. This model has allowed us to recapitulate hematopoietic ontogeny with the ability to control iALL induction at specific developmental stages. We are using single cell genomics to investigate transcriptomic changes during hematopoietic differentiation of our KMT2A:AFF1 iPS cell line. Through this research we expect to discover the genomic and epigenetic landscape and cellular evolution of iALL with the long-term goal to uncover targets specific to iALL for the development of new therapies.

Disciplines

Oncology | Pediatrics

Notes

Presented at the Children's Oncology Group Fall Meeting 2024; New Orleans, LA; September 24-27, 2024.

A Genomics Driven Human Induced Pluripotent Stem Cell Model of Infant ALL – Updates on Hematopoietic Differentiation

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