A novel TLX1-driven T-ALL zebrafish model: comparative genomic analysis with other leukemia models

Loontiens, Siebe; Vanhauwaert, Suzanne; Depestel, Lisa; Dewyn, Givani; Loocke, Wouter Van; Moore, Finola; Garcia, Elaine G.; Batchelor, Lance A.; Borga, Chiara; Squiban, Barbara; Malone-Perez, Megan; Volders, Pieter-Jan; Olexiouk, Volodimir; Vlierberghe, Pieter Van; Langenau, David M.; Frazer, J. Kimble; Durinck, Kaat; Speleman, Franki

doi:10.1038/s41375-020-0938-2

Cited by 7 publications

(8 citation statements)

References 20 publications

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“…In addition, PHF6 mutations have been shown to be associated (at times in conjunction with DNM2) with T-ALLs that overexpress homeobox transcription factors, TLX1 and TLX3 (4, 32, 45). Indeed, ectopic expression of TLX3 in PHF6-deleted mice facilitated early onset leukemia and a hTLX1;PHF6 +/zebrafish model demonstrated fully penetrant early-onset leukemia development, underscoring the role of cooperation between these mutations in leukemogenesis (10,43). Other associations include those with mutations in Xlinked genes, USP9X and MED1 as well as with IL7R-JAK pathway genes, WT1, PTPN2 deletions, and HOX11L2 overexpression (33,34,44,46).…”

Section: T-lymphoblastic Leukemiamentioning

confidence: 98%

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PHF6 Mutations in Hematologic Malignancies

Kurzer

Weinberg

2021

Front. Oncol.

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Next generation sequencing has uncovered several genes with associated mutations in hematologic malignancies that can serve as potential biomarkers of disease. Keeping abreast of these genes is therefore of paramount importance in the field of hematology. This review focuses on PHF6, a highly conserved epigenetic transcriptional regulator that is important for neurodevelopment and hematopoiesis. PHF6 serves as a tumor suppressor protein, with PHF6 mutations and deletions often implicated in the development of T-lymphoblastic leukemia and less frequently in acute myeloid leukemia and other myeloid neoplasms. PHF6 inactivation appears to be an early event in T-lymphoblastic leukemogenesis, requiring cooperating events, including NOTCH1 mutations or overexpression of TLX1 and TLX3 for full disease development. In contrast, PHF6 mutations tend to occur later in myeloid malignancies, are frequently accompanied by RUNX1 mutations, and are often associated with disease progression. Moreover, PHF6 appears to play a role in lineage plasticity within hematopoietic malignancies, with PHF6 mutations commonly present in mixed phenotype acute leukemias with a predilection for T-lineage marker expression. Due to conflicting data, the prognostic significance of PHF6 mutations remains unclear, with a subset of studies showing no significant difference in outcomes compared to malignancies with wild-type PHF6, and other studies showing inferior outcomes in certain patients with mutated PHF6. Future studies are necessary to elucidate the role PHF6 plays in development of T-lymphoblastic leukemia, progression of myeloid malignancies, and its overall prognostic significance in hematopoietic neoplasms.

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Section: T-lymphoblastic Leukemiamentioning

confidence: 98%

“…For example, Miyagi et al did not observe leukemia development subsequent to serial transplantation of PHF6-deleted HSCs in mice (12). Likewise, no T-ALL tumors developed in a PHF6 +/zebrafish model (43).…”

Section: T-lymphoblastic Leukemiamentioning

confidence: 99%

PHF6 Mutations in Hematologic Malignancies

Kurzer

Weinberg

2021

Front. Oncol.

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“…To assess a role for Phf6 in T cell development in vivo , we took advantage of an available phf6 TALEN mutated zebrafish line ( Moore et al, 2012 ; Loontiens et al, 2020 ). Specifically, phf6 mutations were created in exon 2 and resulted in a 10 nucleotide deletion and premature stop codon ( Supplementary Figure 4c ).…”

Section: Resultsmentioning

confidence: 99%

PHF6 Expression Levels Impact Human Hematopoietic Stem Cell Differentiation

Loontiens

Dolens

Strubbe

et al. 2020

Front. Cell Dev. Biol.

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Transcriptional control of hematopoiesis involves complex regulatory networks and functional perturbations in one of these components often results in malignancies. Loss-of-function mutations in PHF6 , encoding a presumed epigenetic regulator, have been primarily described in T cell acute lymphoblastic leukemia (T-ALL) and the first insights into its function in normal hematopoiesis only recently emerged from mouse modeling experiments. Here, we investigated the role of PHF6 in human blood cell development by performing knockdown studies in cord blood and thymus-derived hematopoietic precursors to evaluate the impact on lineage differentiation in well-established in vitro models. Our findings reveal that PHF6 levels differentially impact the differentiation of human hematopoietic progenitor cells into various blood cell lineages, with prominent effects on lymphoid and erythroid differentiation. We show that loss of PHF6 results in accelerated human T cell development through reduced expression of NOTCH1 and its downstream target genes. This functional interaction in developing thymocytes was confirmed in vivo using a phf6 -deficient zebrafish model that also displayed accelerated developmental kinetics upon reduced phf6 or notch1 activation. In summary, our work reveals that appropriate control of PHF6 expression is important for normal human hematopoiesis and provides clues towards the role of PHF6 in T-ALL development.

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“…PHF6 is a highly conserved epigenetic transcriptional regulator, which is important for hematopoiesis and neurodevelopment ( 19 ). However, animal models have revealed that while PHF6 mutations/deletions may be initial events, they are insufficient for tumor initiation without additional driver mutations ( 20 ). Dysfunction of PHF6 usually cooperates with several other driver mutations in the development of leukemia.…”

Section: Discussionmentioning

confidence: 99%

Genomic landscape of T-cell lymphoblastic lymphoma

Song

Zhang

et al. 2022

Chinese Journal of Cancer Research

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Objective T-cell lymphoblastic lymphoma (T-LBL) is an aggressive neoplasm of precursor T cells, however, detailed genome-wide sequencing of large T-LBL cohorts has not been performed due to its rarity. The purpose of this study was to identify putative driver genes in T-LBL. Methods To gain insight into the genetic mechanisms of T-LBL development, we performed whole-exome sequencing on 41 paired tumor-normal DNA samples from patients with T-LBL. Results We identified 32 putative driver genes using whole-exome sequencing in 41 T-LBL cases, many of which have not previously been described in T-LBL, such as Janus kinase 3 ( JAK3 ), Janus kinase 1 ( JAK1 ), Runt-related transcription factor 1 ( RUNX1 ) and Wilms’ tumor suppressor gene 1 ( WT1 ). When comparing the genetic alterations of T-LBL to T-cell acute lymphoblastic leukemia (T-ALL), we found that JAK-STAT and RAS pathway mutations were predominantly observed in T-LBL (58.5% and 34.1%, respectively), whereas Notch and cell cycle signaling pathways mutations were more prevalent in T-ALL. Notably, besides notch receptor 1 ( NOTCH1 ), mutational status of plant homeodomain (PHD)-like finger protein 6 ( PHF6 ) was identified as another independent factor for good prognosis. Of utmost interest is that co-existence of PHF6 and NOTCH1 mutation status might provide an alternative for early therapeutic stratification in T-LBL. Conclusions Together, our findings will not only provide new insights into the molecular and genetic mechanisms of T-LBL, but also have tangible implications for clinical practice.

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A novel TLX1-driven T-ALL zebrafish model: comparative genomic analysis with other leukemia models

Cited by 7 publications

References 20 publications

PHF6 Mutations in Hematologic Malignancies

PHF6 Mutations in Hematologic Malignancies

PHF6 Expression Levels Impact Human Hematopoietic Stem Cell Differentiation

Genomic landscape of T-cell lymphoblastic lymphoma

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