Poster Session II: Acute lymphoblastic leukemia - Biology & translational research
LMO2 is an oncogenic transcription factor that is frequently overexpressed in T-cell acute lymphoblastic leukemia (T-ALL) including poor prognosis Early T-cell Precursor-like ALL (ETP-ALL).
In transgenic mouse models, LMO2 overexpression causes thymocyte self-renewal resulting in T-cell leukemia with long latency. However, the requirement for LMO2 for leukemia maintenance is poorly understood.
1. To develop a regulatable mouse model of LMO2-induced T-ALL.
2. To determine the molecular features associated with LMO2-dependence in T-ALL.
To develop a regulatable model of LMO2-induced T-ALL, LMO2 was cloned downstream of the Tetracycline-regulated element (TRE) promoter (see Figure). To allow us to track LMO2 expression, a Green Fluorescence Protein (GFP) reporter followed by a self-cleaving peptide (P2A) was cloned upstream of LMO2. This construct was knocked into the Col1a1 locus to generate knock-in mice (referred to as TRE-LMO2 mice).
To achieve broad overexpression of LMO2 throughout the hematopoietic system, TRE-LMO2 mice were bred with Vav-tTA transgenic mice, which express the tetracycline transactivator (tTA) downstream of the pan-hematopoietic Vav promoter, to generate Vav-tTA;TRE-LMO2 mice (referred to as VTL mice), in which LMO2 is overexpressed throughout the hematopoietic system and can be repressed by administration of Doxycycline (Dox) (see Figure).
Vav-tTA;TRE-LMO2 mice showed widespread LMO2 overexpression throughout the hematopoietic system. This led to a specific block in T-cell development and to the development of transplantable, self-renewing T-cell progenitors in the thymus from a young age, referred to as preleukemic stem cells (pre-LSCs). This was followed by development of fully penetrant T-lymphoblastic leukemia resembling human T-ALL from 5 months of age.
In preleukemic mice, Dox-induced repression of LMO2 rapidly overcame the T-cell developmental block and eliminated self-renewing pre-LSCs in the thymus. In contrast, LMO2 was dispensable for many LMO2-induced T-cell leukemias and leukemia-derived cell lines, implying an evolution of oncogene addiction in many T-ALLs. LMO2-dependent T-ALL correlated with an immature gene expression profile similar to human ETP-ALL, but could not be predicted by immunophenotype or examination of Notch pathway activation.
We have successfully created a regulatable model of LMO2-driven murine T-ALL.
Whilst continuous LMO2 expression is essential for its preleukemic effects, including T-cell developmental blockade and thymocyte self-renewal, LMO2 is frequently dispensable for maintenance of LMO2-induced murine T-ALL.
LMO2-dependent murine T-ALL has an ETP-like gene expression profile.
The regulatable model presented here will be useful to determine the molecular features associated with LMO2-dependence and critical components of LMO2-induced self-renewal pathways in poor prognosis ETP-ALL.