# Defining and predicting features of lineage-switch potential in KMT2A-r B-ALL using barcoding

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $156,000

## Abstract

PROJECT SUMMARY
Patients with KMT2A-rearranged (KMT2A-r) B-ALL could potentially benefit from the efficacy of CD19 CAR-T
therapy, however they are particularly susceptible to lineage switching (to acute myelogenous leukemia, AML)
upon CD19-directed therapies. However, defining the precise origins and mechanistic basis of “lineage-
switched” leukemia has proven difficult. Clinical studies have previously relied on bulk tumor analysis of
biospecimens obtained pre- and post-CAR-T therapy to infer lineage switching has occurred based on the
presence of naturally occurring genetic footprints (e.g., specific immunoglobulin rearrangements or
translocation breakpoints) in relapsed myeloid CD19neg blasts as evidence of a B-lineage CD19+ origin. These
approaches fail to uncover the clone-specific mechanisms that favor lineage switching throughout CAR-T
pressure directed at the CD19 surface protein. With our newly developed system to transform B cell
progenitors to B-ALL with KMT2A-fusion oncoproteins, we have developed a system that captures the inherent
plasticity of KMT2A-r leukemia. This supplement proposal will rigorously identify leukemia-intrinsic lineage
reprogramming mechanisms though a cellular barcoding and tracking approach that will enable prospective
identification of cell populations that are prone to become the lineage-switched AML in vivo. These studies will
lead to a better understanding of lineage plasticity and the extent to which epigenetic heterogeneity contributes
to the relapsed AML, which can directly inform the design of curative therapies.

## Key facts

- **NIH application ID:** 11074372
- **Project number:** 3R01CA269269-03S1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Patricia Ernst
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $156,000
- **Award type:** 3
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11074372

## Citation

> US National Institutes of Health, RePORTER application 11074372, Defining and predicting features of lineage-switch potential in KMT2A-r B-ALL using barcoding (3R01CA269269-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11074372. Licensed CC0.

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