ONCOGENIC COOPERATION BETWEEN TAL1 EXPRESSION AND PI3K/AKT PATHWAY ACTIVATION IN T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA
Author(s): ,
Naomi Thielemans
Affiliations:
Center for Human Genetics,KU leuven,Leuven,Belgium;Center for Cancer Biology,VIB,Leuven,Belgium
,
Olga gielen
Affiliations:
Center for Human Genetics,KU leuven,Leuven,Belgium;Center for Cancer Biology,VIB,Leuven,Belgium
,
Roel Vandepoel
Affiliations:
Center for Human Genetics,KU leuven,Leuven,Belgium;Center for Cancer Biology,VIB,Leuven,Belgium
Jan Cools
Affiliations:
Center for Human Genetics,KU leuven,Leuven,Belgium;Center for Cancer Biology,VIB,Leuven,Belgium
EHA Library. Thielemans N. Jun 15, 2019; 267224; PS923
Dr. Naomi Thielemans
Dr. Naomi Thielemans
Contributions
Abstract

Abstract: PS923

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic tumor, characterized by high white blood cell counts and infiltration of immature T cells into the bone marrow and other tissues.  T-ALL is caused by the accumulation of multiple genetic defects, including mutually exclusive overexpression of transcription factors (TAL1, TLX1, TLX3 or HOXA), mutations in the NOTCH pathway, IL7R-JAK-STAT pathway or TCR-signaling pathway (AKT, PTEN, RAS). 

TAL1 is aberrantly expressed in up to 40% of T-ALL patients and analysis of sequencing data revealed a significant correlation between TAL1 expression and mutations causing PI3K/AKT pathway activation. This specificity for PI3K/AKT/PTEN mutations in the TAL1 positive T-ALL cases suggests that there could be a synergy between TAL1 expression and PI3K/AKT pathway activation.

Aims
We aimed to study the potential cooperation between TAL1 expression and AKT pathway activation using primary T-cell cultures and mouse models.

Methods

For the in vitro work, we used immature T cells derived from Cre-ER mice that were cultured ex vivo in the presence of Dll4, Scf and Il7. These cells were transduced with inducible vectors containing either TAL1, mutant AKT(E17K) or both. Expression was induced by 4OH-Tamoxifen. For the in vivo work, we used a mouse bone marrow transplantation model. CD2-Cre mice were used as donors and the donor cells were transduced with inducible retroviral vectors containing TAL1, mutant AKT(E17K) or both, which would only be activated by Cre recombinase in CD2 positive cells. Transduced cells were injected in the tail vein of wild type recipient mice to obtain expression of the oncogenes in CD2-positive lymphoid progenitors. ChIP-seq and RNA-seq analysis was performed on the different models. 

Results

Cre-ER expressing Pro-T cells were used to study the effects of TAL1 or AKT(E17K) alone or in combination. Induced expression of TAL1 alone inhibited the growth of pro-T cells. Expression of an AKT(E17K) activating mutant rescued the TAL1 induced growth disadvantage, and the AKT(E17K)/TAL1 double positive pro-T cells were able to proliferate in the absence of Il7. Remarkably, AKT(E17K)/TAL1 double positive pro-T cells showed strong suppression of the JAK/STAT pathway genes indicating a shift towards AKT signalling pathway for survival and proliferation.

We next determined leukemia development using bone marrow transplant assays. Primary transplantation of TAL1 transduced cells did not cause any disease. In contrast, expression of AKT(E17K) alone or TAL1 + AKT(E17K) caused T cell lymphoblastic lymphomas with similar latency (70 days). Relative weight of the mediastinal mass was similar for both groups (450-550 mg). There was no peripheral organ infiltration. The lymphoma cells were of late cortical stage (CD4+CD8+) T cells in both conditions. Lymphoma cells of the TAL1 + AKT(E17K) condition also expressed CD25, a marker of activated T cells.

The TAL1 + AKT(E17K) lymphoma cells were transplantable and caused leukemia with increased white blood cell counts (average: 42,000 cells/mm3), while the AKT only lymphoma cells were not transplantable. 

Conclusion
Our data demonstrate a cooperation between TAL1 and mutant AKT in ex vivo pro-T cell cultures and in mouse bone marrow transplant models.

Session topic: 1. Acute lymphoblastic leukemia - Biology & Translational Research

Keyword(s): Akt, T cell acute lymphoblastic leukemia

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