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

Benjamin J. Shields, Christopher I. Slape, Ngoc Vo, Jacob T. Jackson, Adriana Pliego-Zamora, Hansini Ranasinghe, Wei Shi, David J. Curtis, Matthew P. McCormack

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Number of pages13
JournalLeukemia
DOIs
Publication statusPublished - 1 Jan 2019

Cite this

Shields, Benjamin J. ; Slape, Christopher I. ; Vo, Ngoc ; Jackson, Jacob T. ; Pliego-Zamora, Adriana ; Ranasinghe, Hansini ; Shi, Wei ; Curtis, David J. ; McCormack, Matthew P. / The NUP98-HOXD13 fusion oncogene induces thymocyte self-renewal via Lmo2/Lyl1. In: Leukemia. 2019.
@article{278a2fe05b2e477a89276dfe088bf84a,
title = "The NUP98-HOXD13 fusion oncogene induces thymocyte self-renewal via Lmo2/Lyl1",
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.",
author = "Shields, {Benjamin J.} and Slape, {Christopher I.} and Ngoc Vo and Jackson, {Jacob T.} and Adriana Pliego-Zamora and Hansini Ranasinghe and Wei Shi and Curtis, {David J.} and McCormack, {Matthew P.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1038/s41375-018-0361-0",
language = "English",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Macmillan Publishers",

}

The NUP98-HOXD13 fusion oncogene induces thymocyte self-renewal via Lmo2/Lyl1. / Shields, Benjamin J.; Slape, Christopher I.; Vo, Ngoc; Jackson, Jacob T.; Pliego-Zamora, Adriana; Ranasinghe, Hansini; Shi, Wei; Curtis, David J.; McCormack, Matthew P.

In: Leukemia, 01.01.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The NUP98-HOXD13 fusion oncogene induces thymocyte self-renewal via Lmo2/Lyl1

AU - Shields, Benjamin J.

AU - Slape, Christopher I.

AU - Vo, Ngoc

AU - Jackson, Jacob T.

AU - Pliego-Zamora, Adriana

AU - Ranasinghe, Hansini

AU - Shi, Wei

AU - Curtis, David J.

AU - McCormack, Matthew P.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85060948305&partnerID=8YFLogxK

U2 - 10.1038/s41375-018-0361-0

DO - 10.1038/s41375-018-0361-0

M3 - Article

JO - Leukemia

JF - Leukemia

SN - 0887-6924

ER -