TY - JOUR
T1 - T-ALL can evolve to oncogene independence
AU - Abdulla, Hesham
AU - Vo, Anh
AU - Shields, Benjamin J.
AU - Davies, Tenae J.
AU - Jackson, Jacob T.
AU - Alserihi, Raed
AU - Viney, Elizabeth M.
AU - Wong, Tin
AU - Yan, Feng
AU - Wong, Nicholas C.
AU - Demoen, Lisa
AU - Curtis, David J.
AU - Alexander, Warren S.
AU - Van Vlierberghe, Pieter
AU - Dickins, Ross A.
AU - McCormack, Matthew P.
PY - 2021/1/22
Y1 - 2021/1/22
N2 - The majority of cases of T-cell acute lymphoblastic leukemia (T-ALL) contain chromosomal abnormalities that drive overexpression of oncogenic transcription factors. However, whether these initiating oncogenes are required for leukemia maintenance is poorly understood. To address this, we developed a tetracycline-regulated mouse model of T-ALL driven by the oncogenic transcription factor Lmo2. This revealed that whilst thymus-resident pre-Leukemic Stem Cells (pre-LSCs) required continuous Lmo2 expression, the majority of leukemias relapsed despite Lmo2 withdrawal. Relapse was associated with a mature phenotype and frequent mutation or loss of tumor suppressor genes including Ikzf1 (Ikaros), with targeted deletion Ikzf1 being sufficient to transform Lmo2-dependent leukemias to Lmo2-independence. Moreover, we found that the related transcription factor TAL1 was dispensable in several human T-ALL cell lines that contain SIL-TAL1 chromosomal deletions driving its overexpression, indicating that evolution to oncogene independence can also occur in human T-ALL. Together these results indicate an evolution of oncogene addiction in murine and human T-ALL and show that loss of Ikaros is a mechanism that can promote self-renewal of T-ALL lymphoblasts in the absence of an initiating oncogenic transcription factor.
AB - The majority of cases of T-cell acute lymphoblastic leukemia (T-ALL) contain chromosomal abnormalities that drive overexpression of oncogenic transcription factors. However, whether these initiating oncogenes are required for leukemia maintenance is poorly understood. To address this, we developed a tetracycline-regulated mouse model of T-ALL driven by the oncogenic transcription factor Lmo2. This revealed that whilst thymus-resident pre-Leukemic Stem Cells (pre-LSCs) required continuous Lmo2 expression, the majority of leukemias relapsed despite Lmo2 withdrawal. Relapse was associated with a mature phenotype and frequent mutation or loss of tumor suppressor genes including Ikzf1 (Ikaros), with targeted deletion Ikzf1 being sufficient to transform Lmo2-dependent leukemias to Lmo2-independence. Moreover, we found that the related transcription factor TAL1 was dispensable in several human T-ALL cell lines that contain SIL-TAL1 chromosomal deletions driving its overexpression, indicating that evolution to oncogene independence can also occur in human T-ALL. Together these results indicate an evolution of oncogene addiction in murine and human T-ALL and show that loss of Ikaros is a mechanism that can promote self-renewal of T-ALL lymphoblasts in the absence of an initiating oncogenic transcription factor.
UR - http://www.scopus.com/inward/record.url?scp=85099809432&partnerID=8YFLogxK
U2 - 10.1038/s41375-021-01120-9
DO - 10.1038/s41375-021-01120-9
M3 - Article
C2 - 33483615
AN - SCOPUS:85099809432
JO - Leukemia
JF - Leukemia
SN - 0887-6924
ER -