The NUP98-HOXD13 fusion oncogene induces thymocyte self-renewal via Lmo2/Lyl1

Shields, BJ; Slape, CI; Vo, N; Jackson, JT; Pliego-Zamora, A; Ranasinghe, H; Shi, W; Curtis, DJ; McCormack, MP

Author(s): Shields, BJ; Slape, CI; Vo, N; Jackson, JT; Pliego-Zamora, A; Ranasinghe, H; Shi, W; Curtis, DJ; McCormack, MP;
Details: Publication Year 2019-07-30,Volume 33,Issue #8,Page 1868-1880
Journal Title: Leukemia
Publication Type: Journal Article
Abstract: T cell acute lymphoblastic leukaemia (T-ALL) cases include subfamilies that overexpress the TAL1/LMO, TLX1/3 and HOXA transcription factor oncogenes. While it has been shown that TAL1/LMO transcription factors induce self-renewal of thymocytes, whether this is true for other transcription factor oncogenes is unknown. To address this, we have studied NUP98-HOXD13-transgenic (NHD13-Tg) mice, which overexpress HOXA transcription factors throughout haematopoiesis and develop both myelodysplastic syndrome (MDS) progressing to acute myeloid leukaemia (AML) as well as T-ALL. We find that thymocytes from preleukaemic NHD13-Tg mice can serially transplant, demonstrating that they have self-renewal capacity. Transcriptome analysis shows that NHD13-Tg thymocytes exhibit a stem cell-like transcriptional programme closely resembling that induced by Lmo2, including Lmo2 itself and its critical cofactor Lyl1. To determine whether Lmo2/Lyl1 are required for NHD13-induced thymocyte self-renewal, NHD13-Tg mice were crossed with Lyl1 knockout mice. This showed that Lyl1 is essential for expression of the stem cell-like gene expression programme in thymocytes and self-renewal. Surprisingly however, NHD13 transgenic mice lacking Lyl1 showed accelerated T-ALL and absence of transformation to AML, associated with a loss of multipotent progenitors in the bone marrow. Thus multiple T cell oncogenes induce thymocyte self-renewal via Lmo2/Lyl1; however, NHD13 can also promote T-ALL via an alternative pathway.
Publisher: Springer Nature
Research Division(s): Bioinformatics
PubMed ID: 30700838
Publisher's Version: https://doi.org/10.1038/s41375-018-0361-0
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2019-03-13 08:04:19

Last Modified: 2019-08-23 02:23:59