Small molecule inhibits T-cell acute lymphoblastic leukaemia oncogenic interaction through conformational modulation of LMO2.

Leanne Milton-Harris,Sarah A Walker,Simon E Ward,Mark Jeeves,Erika J Mancini

doi:10.18632/oncotarget.27580

Leanne Milton-Harris, Sarah A Walker + Show 3 more

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https://doi.org/10.18632/oncotarget.27580

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Abstract

Ectopic expression in T-cell precursors of LIM only protein 2 (LMO2), a key factor in hematopoietic development, has been linked to the onset of T-cell acute lymphoblastic leukaemia (T-ALL). In the T-ALL context, LMO2 drives oncogenic progression through binding to erythroid-specific transcription factor SCL/TAL1 and sequestration of E-protein transcription factors, normally required for T-cell differentiation. A key requirement for the formation of this oncogenic protein-protein interaction (PPI) is the conformational flexibility of LMO2. Here we identify a small molecule inhibitor of the SCL-LMO2 PPI, which hinders the interaction in vitro through direct binding to LMO2. Biophysical analysis demonstrates that this inhibitor acts through a mechanism of conformational modulation of LMO2. Importantly, this work has led to the identification of a small molecule inhibitor of the SCL-LMO2 PPI, which can provide a starting point for the development of new agents for the treatment of T-ALL. These results suggest that similar approaches, based on the modulation of protein conformation by small molecules, might be used for therapeutic targeting of other oncogenic PPIs.

Highlights

Stem cell leukaemia (SCL, known as TAL1) is a basic helix-loop-helix transcription factor with essential, non-redundant roles in haematopoietic development and the terminal maturation of erythroid cell lineages [1, 2]
Aberrant LIM only protein 2 (LMO2) expression due to chromosomal translocations or interstitial deletions [11,12,13] has been observed in multiple haematological malignancies, most notably T-cell acute lymphoblastic leukaemia (T-ALL) [4, 14]
Using Small Angle X-ray Scattering (SAXS) we demonstrate that 3K7 acts through a mechanism of structural modulation, locking LMO2 in a conformation that inhibits its interactions with SCL

Summary

Introduction

Stem cell leukaemia (SCL, known as TAL1) is a basic helix-loop-helix transcription factor with essential, non-redundant roles in haematopoietic development and the terminal maturation of erythroid cell lineages [1, 2]. Central to SCL function is the ability to bind the haematopoietic transcription co-factor LIMonly protein 2 (LMO2) [3]. LMO2 has multiple essential roles in erythroid differentiation, angiogenesis and CNS development [4,5,6,7,8,9,10]. Aberrant LMO2 expression due to chromosomal translocations or interstitial deletions [11,12,13] has been observed in multiple haematological malignancies, most notably T-cell acute lymphoblastic leukaemia (T-ALL) [4, 14]. Dysregulation of LMO2 alone through somatic mutation [18] or resulting from retroviral activation mutagenesis following treatment for X-SCID [19] is recognised as an oncogenic promoter in T-ALL

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