Cell models of infant acute lymphoblastic leukemia
Presenter Status
Staff
Abstract Type
Basic Research
Primary Mentor or Principal Investigator
Jay Vivian
Presentation Type
Poster
Start Date
20-5-2026 11:00 AM
End Date
20-5-2026 12:00 PM
Abstract Text
Background:
Chromosomal rearrangements involving KMT2A (KMT2A-r) occur in acute lymphoblastic leukemia (ALL). KMT2A-r generates a fusion oncogene and is the driver mutation in 70% of infants with ALL (iALL). KMT2A-r is highly prognostic of poor survival in iALL (approximately 40%) and is associated with higher risks of chemoresistance, relapse, and death due to disease. Cellular pathways influencing resistance to standard of care chemotherapeutics and investigational drugs such as menin inhibitors in pediatric KMT2A-r leukemias remain poorly understood. iALL expressing MLL-AFF1 is an unusual cancer in that other somatic mutations are uncommon and there are no known genetic risk factors. iALL originates in utero and associated with an 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. The response of infant onset leukemia to existing chemotherapeutics is poor, thus new strategies need to be explored.
Objectives/Goal:
Our collaborative studies aim to develop and study several in vitro models of iALL. The goals for these models are to define the earliest events of leukemic initiation, drivers of progression, and use in novel therapeutic assessment. Modulation of autophagy is a focus of our therapeutic assessment and improvement of current therapies, given that inhibition of autophagy has been shown to enhance the response of cells to certain chemotherapeutics.
Methods/Design:
We have created a highly controlled induced pluripotent stem (iPS) cell model system to understand the earliest molecular events of leukemogenesis in iALL. We engineered human iPS cell lines to express ML-Aff1 fusion and have used directed differentiation to produce functional human hematopoietic stem and progenitor (HSPCs) and lymphoid progenitors from iPS cells. The differentiation is being assessed via a series of single cell transcriptomic and bulk RNA sequencing analyses. Leukemia cancer cell lines derived from iALL have also been obtained and are being examined for sensitivity to standard of care therapies, investigational new drugs, and autophagy modulators.
Results:
Single cell transcriptomics has shown that our iPS cell differentiation platform accurately recapitulates early hematopoietic differentiation programs in the embryo and fetus. The iPS cell-based iALL cell model system has uncovered novel early gene expression response to the KMT2A oncogenic driver. Analysis of the iALL cancer cell lines to a survey of 1600 FDA approved compounds demonstrated sensitivity to a range of compounds.
Conclusions:
These models demonstrate accurate recapitulation of many aspects of hematopoietic differentiation, iALL progression, and drug response. 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. Our analysis of the response of these cells to these drugs provide a foundational baseline for future drug screens.
Cell models of infant acute lymphoblastic leukemia
Background:
Chromosomal rearrangements involving KMT2A (KMT2A-r) occur in acute lymphoblastic leukemia (ALL). KMT2A-r generates a fusion oncogene and is the driver mutation in 70% of infants with ALL (iALL). KMT2A-r is highly prognostic of poor survival in iALL (approximately 40%) and is associated with higher risks of chemoresistance, relapse, and death due to disease. Cellular pathways influencing resistance to standard of care chemotherapeutics and investigational drugs such as menin inhibitors in pediatric KMT2A-r leukemias remain poorly understood. iALL expressing MLL-AFF1 is an unusual cancer in that other somatic mutations are uncommon and there are no known genetic risk factors. iALL originates in utero and associated with an 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. The response of infant onset leukemia to existing chemotherapeutics is poor, thus new strategies need to be explored.
Objectives/Goal:
Our collaborative studies aim to develop and study several in vitro models of iALL. The goals for these models are to define the earliest events of leukemic initiation, drivers of progression, and use in novel therapeutic assessment. Modulation of autophagy is a focus of our therapeutic assessment and improvement of current therapies, given that inhibition of autophagy has been shown to enhance the response of cells to certain chemotherapeutics.
Methods/Design:
We have created a highly controlled induced pluripotent stem (iPS) cell model system to understand the earliest molecular events of leukemogenesis in iALL. We engineered human iPS cell lines to express ML-Aff1 fusion and have used directed differentiation to produce functional human hematopoietic stem and progenitor (HSPCs) and lymphoid progenitors from iPS cells. The differentiation is being assessed via a series of single cell transcriptomic and bulk RNA sequencing analyses. Leukemia cancer cell lines derived from iALL have also been obtained and are being examined for sensitivity to standard of care therapies, investigational new drugs, and autophagy modulators.
Results:
Single cell transcriptomics has shown that our iPS cell differentiation platform accurately recapitulates early hematopoietic differentiation programs in the embryo and fetus. The iPS cell-based iALL cell model system has uncovered novel early gene expression response to the KMT2A oncogenic driver. Analysis of the iALL cancer cell lines to a survey of 1600 FDA approved compounds demonstrated sensitivity to a range of compounds.
Conclusions:
These models demonstrate accurate recapitulation of many aspects of hematopoietic differentiation, iALL progression, and drug response. 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. Our analysis of the response of these cells to these drugs provide a foundational baseline for future drug screens.
Comments
Restricted to Title/Author List/Abstract only as requested by primary author
Poster Board Number: 36