The molecular basis of Lmo2-induced T-cell acute lymphoblastic leukemia.
T-cell acute lymphoblastic leukemia (T-ALL) is commonly caused by the overexpression of oncogenic transcription factors in developing T cells. In a mouse model of one such oncogene, LMO2, the cellular effect is to induce self-renewal of committed T cells in the thymus, which persist long-term while acquiring additional mutations and eventually giving rise to leukemia. These precancerous stem cells (pre-CSC) are intrinsically resistant to radiotherapy, implying that they may be refractory to conventional cancer therapies. However, they depend on an aberrantly expressed stem cell-like self-renewal program for their maintenance, in addition to a specialized thymic microenvironmental niche. Here, we discuss potential approaches for targeting pre-CSCs in T-ALL by using therapies directed at oncogenic transcription factors themselves, downstream self-renewal pathways, and the supportive cell niche.
Curtis
David J
DJ
Rotary Bone Marrow Research Laboratories, Royal Melbourne Hospital, University of Melbourne, Parkville, Australia.
McCormack
Matthew P
MP
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004195:Disease Models, Animal; D006801:Humans; D060588:LIM Domain Proteins; D008667:Metalloproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055153:Stem Cell Niche / Q000378:metabolism / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C513188:Lmo2 protein, mouse; D008667:Metalloproteins