Requirement for Lyl1 in a model of Lmo2-driven early T-cell precursor ALL

Abstract

Key Points• Lyl1 is required for Lmo2-induced T-cell leukemia in mice, whereas Scl is dispensable.• LYL1 is required for growth of ETP-ALL cell lines.Lmo2 is an oncogenic transcription factor that is frequently overexpressed in T-cell acute lymphoblastic leukemia (T-ALL), including early T-cell precursor ALL (ETP-ALL) cases with poor prognosis. Lmo2 must be recruited to DNA by binding to the hematopoietic basic helix-loop-helix factors Scl/Tal1 or Lyl1. However, it is unknown which of these factors can mediate the leukemic activity of Lmo2. To address this, we have generated Lmo2-transgenic mice lacking either Scl or Lyl1 in the thymus. We show that although Scl is dispensable for Lmo2-driven leukemia, Lyl1 is critical for all oncogenic functions of Lmo2, including upregulation of a stem cell-like gene signature, aberrant self-renewal of thymocytes, and subsequent generation of T-cell leukemia. Lyl1 expression is restricted to preleukemic and leukemic stem cell populations in this model, providing a molecular explanation for the stage-specific expression of the Lmo2-induced gene expression program. Moreover, LMO2 and LYL1 are coexpressed in ETP-ALL patient samples, and LYL1 is required for growth of ETP-ALL cell lines. Thus, the LMO2-LYL1 interaction is a promising therapeutic target for inhibiting self-renewing cancer stem cells in T-ALL, including poor-prognosis ETP-ALL cases. (Blood. 2013;122(12):2093-2103

Hhex induces promyelocyte self-renewal and cooperates with growth factor independence to cause myeloid leukemia in mice

“…12,13 Accordingly, Hhex expression is strongly associated with early T-cell precursor-like acute lymphoblastic leukemia in humans. 38 Our present results suggest that Hhex overexpression may block differentiation and promote selfrenewal in myeloid and T-cell leukemias by similar mechanisms.…”

A crucial role for the homeodomain transcription factor Hhex in lymphopoiesis

“…This is likely to be due to compensatory expansion of T cells within thymic niches vacated by the absence of Hhex 2/D ETPs, as described in a number of knockout mice models with incomplete blocks in thymus seeding or early T-cell development. 35,36 Interestingly, although Hhex is only expressed until the DN2 stage of T-cell development, 26 in vivo T-cell development from Hhex 2/D LSK cells continued to decline after this stage culminating in a 15-fold decrease in peripheral T cells. Together, these data indicate a persistent defect in T-cell progenitors in the absence of Hhex.…”

High-throughput screening in niche-based assay identifies compounds to target preleukemic stem cells

“…In contrast, SCL activation in thymocytes occurs in a context whereby other self-renewal genes are absent and therefore preLSCs are "addicted" to SCL. Along the same line, Lyl1 upregulation by Lmo2 in DN3 thymocytes occurs in a context whereby Scl is not expressed, and therefore Lyl1 is required for Lmo2 reprogramming activity (70). Similarly, Myc is critical for pre-LSC selfrenewal activity (14,56), whereas Myc is redundant in HSCs (71), indicating that targeting MYC will spare normal HSCs.…”