Perspective Controlling Pre-leukemic Thymocyte Self-Renewal

T cell acute lymphoblastic leukemia (T-ALL) develops in a multistep process whereby thymic progenitor cells gradually accumulate genetic and epigenetic chang-es, eventually leading to fully transformed immature lymphoblasts. Aberrant activa-tion of transcription factor oncogenes is considered a core component of the oncogenic program that drives malignant T cell transformation. For example, the TAL1 (SCL) and LYL1 basic Helix-Loop-Helix (bHLH) transcription factors, as well as the LIM domain–only proteins LMO1 or LMO2, are activated by chromosomal translocations or interstitial deletions in a large fraction of primary T-ALLs. Nota-bly, these leukemias often present with activating NOTCH1 mutations, suggesting that enhanced NOTCH signaling and aberrant TAL1, LYL1, LMO1, and/or LMO2 expression are collaborative events in the multistep pathogenesis of T-ALL [1,2]. Recent experimental evidence un-covered the existence of long-lived pre-leukemic stem cells (pre-LSCs) with self-renewal properties, allowing clonal expan-sion and subsequent acquisition of onco-genic mutations leading to cancer [3,4]. For example, DNMT3A mutant pre-LSCs were shown to survive chemotherapy and represent a reservoir for leukemic progres-sion and hematological relapse in acute myeloid leukemia (AML) [5,6]. Although the concept of pre-leukemic stem cells has been previously proposed in the context of T-ALL [7], the actual molecular mecha-nisms by which T cell-specific oncogenes regulate pre-LSC activity of thymic pre-cursors remains largely unexplored. Nota-bly, these mechanistic insights could pro-vide valuable input for the development of novel therapeutic strategies that can effec-tively eradicate quiescent and therapy-resistant clones [4,6,7]. Pre-leukemic Stem Cells: It’s Al