TAL1 and LMO2 Promote Leukemia-Initiating Cell Quiescence and Chemotolerance in T-ALL

Abstract

Relapse remains a major barrier to the successful treatment of children with T-cell acute lymphoblastic leukemia (T-ALL) and may represent a failure to eliminate leukemia-initiating cells (L-ICs) that possess distinguishing biological features from the bulk leukemic population. TAL1 and LMO2 are often coordinately misexpressed in T-ALL patients and their ectopic expression cooperates to transform thymic progenitors in mice. In this model, double negative-3 (DN3) stage thymic progenitors harbor L-ICs, yet only a subset of DN3 leukemic cells have L-IC activity. We interrogated L-IC heterogeneity in our Tal1/Lmo2 mouse T-ALL model using a combination of single cell RNA-sequencing (scRNA-seq) and H2B-GFP nucleosome labeling. We identified a cell cycle restricted DN3 subpopulation with high Notch1 activity and enrichment of Tal1/Lmo2 targets and T-cell quiescence genes. This dormant DN3 population significantly increased during leukemogenesis, exhibited chemotolerance and was enriched for genes associated with patient minimal residual disease (MRD). In vivo studies using the Tet-inducible H2B-GFP model revealed that Tal1 and Lmo2 cooperate to promote quiescence in DN3 cells. Examination of TAL1/LMO patient samples revealed that the L-IC enriched CD7+CD1a- thymic progenitors (hL-IC) were also chemotolerant and were also variably associated with quiescence. Collectively, our results document the emergence of dormant and chemotolerant L-ICs during Tal1/Lmo2-induced leukemogenesis in mice and relapsed T-ALL patients.