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Article ; Online: Myb

Almeida, André / T'Sas, Sara / Pagliaro, Luca / Fijalkowski, Igor / Sleeckx, Wouter / Van Steenberge, Hannah / Zamponi, Raffaella / Lintermans, Béatrice / Van Loocke, Wouter / Palhais, Bruno / Reekmans, Alexandra / Bardelli, Valentina / Demoen, Lisa / Reunes, Lindy / Deforce, Dieter / Van Nieuwerburgh, Filip / Kentsis, Alex / Ntziachristos, Panagiotis / Van Roy, Nadine /

De Moerloose, Barbara / Mecucci, Cristina / La Starza, Roberta / Roti, Giovanni / Goossens, Steven / Van Vlierberghe, Pieter / Pieters, Tim

HemaSphere

2024 Volume 8, Issue 3, Page(s) e51

Abstract: T-lineage acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that accounts for 10%-15% of pediatric and 25% of adult ALL cases. Although the prognosis of T-ALL has improved over time, the outcome of T-ALL patients with primary ...

Abstract	T-lineage acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that accounts for 10%-15% of pediatric and 25% of adult ALL cases. Although the prognosis of T-ALL has improved over time, the outcome of T-ALL patients with primary resistant or relapsed leukemia remains poor. Therefore, further progress in the treatment of T-ALL requires a better understanding of its biology and the development of more effective precision oncologic therapies. The proto-oncogene
Language	English
Publishing date	2024-03-10
Publishing country	United States
Document type	Journal Article
ISSN	2572-9241
ISSN (online)	2572-9241
DOI	10.1002/hem3.51
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Article ; Online: T-ALL can evolve to oncogene independence.

Abdulla, Hesham / Vo, Anh / Shields, Benjamin J / Davies, Tenae J / Jackson, Jacob T / Alserihi, Raed / Viney, Elizabeth M / Wong, Tin / Yan, Feng / Wong, Nicholas C / Demoen, Lisa / Curtis, David J / Alexander, Warren S / Van Vlierberghe, Pieter / Dickins, Ross A / McCormack, Matthew P

Leukemia

2021 Volume 35, Issue 8, Page(s) 2205–2219

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Adaptor Proteins, Signal Transducing/physiology ; Animals ; Gene Expression Regulation, Leukemic ; Ikaros Transcription Factor/physiology ; LIM Domain Proteins/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Oncogenes ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/etiology ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology
Chemical Substances	Adaptor Proteins, Signal Transducing ; LIM Domain Proteins ; Lmo2 protein, mouse ; Zfpn1a1 protein, mouse ; Ikaros Transcription Factor (148971-36-2)
Language	English
Publishing date	2021-01-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-021-01120-9
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Article ; Online: CASZ1 upregulates PI3K-AKT-mTOR signaling and promotes T-cell acute lymphoblastic leukemia.

Cardoso, Bruno A / Duque, Mafalda / Gírio, Ana / Fragoso, Rita / Oliveira, Mariana L / Allen, James R / Martins, Leila R / Correia, Nádia C / Silveira, André Bortolini / Veloso, Alexandra / Kimura, Shunsuke / Demoen, Lisa / Matthijssens, Filip / Jeha, Sima / Cheng, Cheng / Pui, Ching-Hon / Grosso, Ana R / Neto, João L / De Almeida, Sérgio F /

Van Vlieberghe, Pieter / Mullighan, Charles G / Yunes, J Andres / Langenau, David M / Pflumio, Françoise / Barata, João T

Haematologica

2023

Abstract: CASZ1 is a conserved transcription factor involved in neural development, blood vessel assembly and heart morphogenesis. CASZ1 has been implicated in cancer, either suppressing or promoting tumor development depending on the tissue. However, the impact ... ...

Abstract	CASZ1 is a conserved transcription factor involved in neural development, blood vessel assembly and heart morphogenesis. CASZ1 has been implicated in cancer, either suppressing or promoting tumor development depending on the tissue. However, the impact of CASZ1 on hematological tumors remains unknown. Here, we show that the T-cell oncogenic transcription factor TAL1 is a direct positive regulator of CASZ1, that T-cell acute lymphoblastic leukemia (T-ALL) samples at diagnosis overexpress CASZ1b isoform, and that CASZ1b expression in patient samples correlates with PI3KAKT- mTOR signaling pathway activation. In agreement, overexpression of CASZ1b in both Ba/F3 and T-ALL cells leads to the activation of PI3K signaling pathway, which is required for CASZ1b-mediated transformation of Ba/F3 cells in vitro and malignant expansion in vivo. We further demonstrate that CASZ1b cooperates with activated NOTCH1 to promote T-ALL development in zebrafish, and that CASZ1b protects human T-ALL cells from serum deprivation and treatment with chemotherapeutic drugs. Taken together, our studies indicate that CASZ1b is a TAL1-regulated gene that promotes T-ALL development and resistance to chemotherapy.
Language	English
Publishing date	2023-12-07
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2023.282854
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Article ; Online: Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting.

Science advances

2021 Volume 7, Issue 13

Abstract: The therapeutic scope of antibody and nonantibody protein scaffolds is still prohibitively limited against intracellular drug targets. Here, we demonstrate that the Alphabody scaffold can be engineered into a cell-penetrating protein antagonist against ... ...

Abstract	The therapeutic scope of antibody and nonantibody protein scaffolds is still prohibitively limited against intracellular drug targets. Here, we demonstrate that the Alphabody scaffold can be engineered into a cell-penetrating protein antagonist against induced myeloid leukemia cell differentiation protein MCL-1, an intracellular target in cancer, by grafting the critical B-cell lymphoma 2 homology 3 helix of MCL-1 onto the Alphabody and tagging the scaffold's termini with designed cell-penetration polypeptides. Introduction of an albumin-binding moiety extended the serum half-life of the engineered Alphabody to therapeutically relevant levels, and administration thereof in mouse tumor xenografts based on myeloma cell lines reduced tumor burden. Crystal structures of such a designed Alphabody in complex with MCL-1 and serum albumin provided the structural blueprint of the applied design principles. Collectively, we provide proof of concept for the use of Alphabodies against intracellular disease mediators, which, to date, have remained in the realm of small-molecule therapeutics.
MeSH term(s)	Animals ; Apoptosis ; Cell Line ; Cell Line, Tumor ; Drug Delivery Systems ; Humans ; Mice ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Neoplasms ; Peptides/chemistry
Chemical Substances	Myeloid Cell Leukemia Sequence 1 Protein ; Peptides
Language	English
Publishing date	2021-03-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abe1682
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Article ; Online: Novel strategy for rapid functional in vivo validation of oncogenic drivers in haematological malignancies.

Pieters, Tim / T'Sas, Sara / Demoen, Lisa / Almeida, André / Haenebalcke, Lieven / Matthijssens, Filip / Lemeire, Kelly / D'Hont, Jinke / Van Rockeghem, Frederique / Hochepied, Tino / Lintermans, Beatrice / Reunes, Lindy / Lammens, Tim / Berx, Geert / Haigh, Jody J / Goossens, Steven / Van Vlierberghe, Pieter

Scientific reports

2019 Volume 9, Issue 1, Page(s) 10577

Abstract: In cancer research, it remains challenging to functionally validate putative novel oncogenic drivers and to establish relevant preclinical models for evaluation of novel therapeutic strategies. Here, we describe an optimized and efficient pipeline for ... ...

Abstract	In cancer research, it remains challenging to functionally validate putative novel oncogenic drivers and to establish relevant preclinical models for evaluation of novel therapeutic strategies. Here, we describe an optimized and efficient pipeline for the generation of novel conditional overexpression mouse models in which putative oncogenes, along with an eGFP/Luciferase dual reporter, are expressed from the endogenous ROSA26 (R26) promoter. The efficiency of this approach was demonstrated by the generation and validation of novel R26 knock-in (KI) mice that allow conditional overexpression of Jarid2, Runx2, MN1 and a dominant negative allele of ETV6. As proof of concept, we confirm that MN1 overexpression in the hematopoietic lineage is sufficient to drive myeloid leukemia. In addition, we show that T-cell specific activation of MN1 in combination with loss of Pten increases tumour penetrance and stimulates the formation of Lyl1
MeSH term(s)	Animals ; Core Binding Factor Alpha 1 Subunit/genetics ; Female ; Gene Knock-In Techniques ; Genes, Reporter ; Hematologic Neoplasms/etiology ; Hematologic Neoplasms/genetics ; Humans ; Leukemia/etiology ; Leukemia/genetics ; Leukemia, Myeloid/genetics ; Male ; Mice ; Mice, Transgenic ; Neoplasm Transplantation ; Oncogenes/genetics ; Polycomb Repressive Complex 2/genetics ; Trans-Activators/genetics ; Tumor Suppressor Proteins/genetics
Chemical Substances	Core Binding Factor Alpha 1 Subunit ; Jarid2 protein, mouse ; Mn1 protein, mouse ; Runx2 protein, mouse ; Trans-Activators ; Tumor Suppressor Proteins ; Polycomb Repressive Complex 2 (EC 2.1.1.43)
Language	English
Publishing date	2019-07-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-46853-x
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Article ; Online: RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia.

Matthijssens, Filip / Sharma, Nitesh D / Nysus, Monique / Nickl, Christian K / Kang, Huining / Perez, Dominique R / Lintermans, Beatrice / Van Loocke, Wouter / Roels, Juliette / Peirs, Sofie / Demoen, Lisa / Pieters, Tim / Reunes, Lindy / Lammens, Tim / De Moerloose, Barbara / Van Nieuwerburgh, Filip / Deforce, Dieter L / Cheung, Laurence C / Kotecha, Rishi S /

Risseeuw, Martijn Dp / Van Calenbergh, Serge / Takarada, Takeshi / Yoneda, Yukio / van Delft, Frederik W / Lock, Richard B / Merkley, Seth D / Chigaev, Alexandre / Sklar, Larry A / Mullighan, Charles G / Loh, Mignon L / Winter, Stuart S / Hunger, Stephen P / Goossens, Steven / Castillo, Eliseo F / Ornatowski, Wojciech / Van Vlierberghe, Pieter / Matlawska-Wasowska, Ksenia

The Journal of clinical investigation

2021 Volume 131, Issue 6

Abstract: T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with inferior outcome compared with that of B cell ALL. Here, we show that Runt-related transcription factor 2 (RUNX2) was upregulated in high-risk T-ALL with KMT2A ... ...

Abstract	T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with inferior outcome compared with that of B cell ALL. Here, we show that Runt-related transcription factor 2 (RUNX2) was upregulated in high-risk T-ALL with KMT2A rearrangements (KMT2A-R) or an immature immunophenotype. In KMT2A-R cells, we identified RUNX2 as a direct target of the KMT2A chimeras, where it reciprocally bound the KMT2A promoter, establishing a regulatory feed-forward mechanism. Notably, RUNX2 was required for survival of immature and KMT2A-R T-ALL cells in vitro and in vivo. We report direct transcriptional regulation of CXCR4 signaling by RUNX2, thereby promoting chemotaxis, adhesion, and homing to medullary and extramedullary sites. RUNX2 enabled these energy-demanding processes by increasing metabolic activity in T-ALL cells through positive regulation of both glycolysis and oxidative phosphorylation. Concurrently, RUNX2 upregulation increased mitochondrial dynamics and biogenesis in T-ALL cells. Finally, as a proof of concept, we demonstrate that immature and KMT2A-R T-ALL cells were vulnerable to pharmacological targeting of the interaction between RUNX2 and its cofactor CBFβ. In conclusion, we show that RUNX2 acts as a dependency factor in high-risk subtypes of human T-ALL through concomitant regulation of tumor metabolism and leukemic cell migration.
MeSH term(s)	Animals ; Cell Line, Tumor ; Chemotaxis, Leukocyte ; Child ; Core Binding Factor Alpha 1 Subunit/genetics ; Core Binding Factor Alpha 1 Subunit/metabolism ; Core Binding Factor beta Subunit/metabolism ; Disease Progression ; Gene Expression Regulation, Developmental ; Gene Expression Regulation, Neoplastic ; Gene Rearrangement ; Hematopoiesis ; Histone-Lysine N-Methyltransferase/genetics ; Histone-Lysine N-Methyltransferase/metabolism ; Humans ; In Vitro Techniques ; Mice ; Myeloid-Lymphoid Leukemia Protein/genetics ; Myeloid-Lymphoid Leukemia Protein/metabolism ; Organelle Biogenesis ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Receptors, CXCR4/metabolism ; Signal Transduction
Chemical Substances	CBFB protein, human ; CXCR4 protein, human ; Core Binding Factor Alpha 1 Subunit ; Core Binding Factor beta Subunit ; KMT2A protein, human ; RNA, Messenger ; RUNX2 protein, human ; Receptors, CXCR4 ; Myeloid-Lymphoid Leukemia Protein (149025-06-9) ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43)
Language	English
Publishing date	2021-02-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI141566
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Article ; Online: Aging of preleukemic thymocytes drives CpG island hypermethylation in T-cell acute lymphoblastic leukemia.

Roels, Juliette / Thénoz, Morgan / Szarzyńska, Bronisława / Landfors, Mattias / De Coninck, Stien / Demoen, Lisa / Provez, Lien / Kuchmiy, Anna / Strubbe, Steven / Reunes, Lindy / Pieters, Tim / Matthijssens, Filip / Van Loocke, Wouter / Erarslan-Uysal, Büşra / Richter-Pechańska, Paulina / Declerck, Ken / Lammens, Tim / De Moerloose, Barbara / Deforce, Dieter /

Van Nieuwerburgh, Filip / Cheung, Laurence C / Kotecha, Rishi S / Mansour, Marc R / Ghesquière, Bart / Van Camp, Guy / Berghe, Wim Vanden / Kowalczyk, Jerzy R / Szczepański, Tomasz / Davé, Utpal P / Kulozik, Andreas E / Goossens, Steven / Curtis, David J / Taghon, Tom / Dawidowska, Małgorzata / Degerman, Sofie / Van Vlierberghe, Pieter

Blood cancer discovery

2020 Volume 1, Issue 3, Page(s) 274–289

Abstract: Cancer cells display DNA hypermethylation at specific CpG islands in comparison to their normal healthy counterparts, but the mechanism that drives this so-called CpG island methylator phenotype (CIMP) remains poorly understood. Here, we show that CpG ... ...

Abstract	Cancer cells display DNA hypermethylation at specific CpG islands in comparison to their normal healthy counterparts, but the mechanism that drives this so-called CpG island methylator phenotype (CIMP) remains poorly understood. Here, we show that CpG island methylation in human T-cell acute lymphoblastic leukemia (T-ALL) mainly occurs at promoters of Polycomb Repressor Complex 2 (PRC2) target genes that are not expressed in normal or malignant T-cells and which display a reciprocal association with H3K27me3 binding. In addition, we revealed that this aberrant methylation profile reflects the epigenetic history of T-ALL and is established already in pre-leukemic, self-renewing thymocytes that precede T-ALL development. Finally, we unexpectedly uncover that this age-related CpG island hypermethylation signature in T-ALL is completely resistant to the FDA-approved hypomethylating agent Decitabine. Altogether, we here provide conceptual evidence for the involvement of a pre-leukemic phase characterized by self-renewing thymocytes in the pathogenesis of human T-ALL.
MeSH term(s)	Aging ; CpG Islands/genetics ; DNA Methylation/genetics ; Humans ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Thymocytes
Language	English
Publishing date	2020-09-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3028898-8
ISSN	2643-3249 ; 2643-3230
ISSN (online)	2643-3249
ISSN	2643-3230
DOI	10.1158/2643-3230.BCD-20-0059
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Article ; Online: Myb

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Article ; Online: T-ALL can evolve to oncogene independence.

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Article ; Online: CASZ1 upregulates PI3K-AKT-mTOR signaling and promotes T-cell acute lymphoblastic leukemia.

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Article ; Online: Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting.

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Article ; Online: Novel strategy for rapid functional in vivo validation of oncogenic drivers in haematological malignancies.

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Article ; Online: RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia.

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Article ; Online: Aging of preleukemic thymocytes drives CpG island hypermethylation in T-cell acute lymphoblastic leukemia.

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