The NUP98-HOXD13 fusion oncogene induces thymocyte self-renewal via Lmo2/Lyl1.
Benjamin J ShieldsChristopher I SlapeNgoc VoJacob T JacksonAdriana Pliego-ZamoraHansini RanasingheWei ShiDavid J CurtisMatthew P McCormackPublished in: Leukemia (2019)
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.
Keyphrases
- transcription factor
- stem cells
- gene expression
- bone marrow
- acute myeloid leukemia
- dna binding
- high fat diet induced
- liver failure
- poor prognosis
- long non coding rna
- randomized controlled trial
- aortic dissection
- mesenchymal stem cells
- study protocol
- intensive care unit
- metabolic syndrome
- clinical trial
- type diabetes
- skeletal muscle
- binding protein