Recurrent DGCR8, DROSHA, and SIX Homeodomain Mutations in Favorable Histology Wilms Tumors

Walz, Amy L.; Ooms, Ariadne H.A.G.; Gadd, Samantha; Gerhard, Daniela S.; Smith, Malcolm A.; Guidry-Auvil, Jaime; Meerzaman, Daoud; Chen, Qing Rong; Hsu, Chih Hao; Yan, Chunhua; Nguyen, Cu; Hu, Ying; Bowlby, Reanne; Brooks, Denise; Ma, Yussanne; Mungall, Andrew J.; Moore, Richard A.; Schein, Jacqueline E.; Marra, Marco A.; Huff, Vicki; Dome, Jeffrey S.; Yun, Yueh; Mullighan, Charles G.; Ma, Jing; Wheeler, David A.; Hampton, Oliver A.; Jafari, Nadereh; Ross, Nicole; Gastier‐Foster, Julie M.; Perlman, Elizabeth J.

doi:10.1016/j.ccell.2015.02.008

Cited by 49 publications

(108 citation statements)

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“…21 Moreover, Six1 is overexpressed in For panels E-G, n = 3, one-way ANOVA, *P < 0.05; **P < 0.01; ***P < 0.001 various solid tumors, such as cervical cancer, 31,45 hepatocellular carcinoma 28,44 and Wilms tumors. 46,47 We also observed the highly increased expression of Six1 in AML patients, especially in MLL-rearranged AML. Taken together, these studies suggest an oncogenic role of Six1 in various cancers.…”

Section: Discussionsupporting

confidence: 54%

Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia

Chu

Chen

et al. 2019

Cancer Science

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Molecular genetic changes in acute myeloid leukemia (AML) play crucial roles in leukemogenesis, including recurrent chromosome translocations, epigenetic/spliceosome mutations and transcription factor aberrations. Six1, a transcription factor of the Sine oculis homeobox (Six) family, has been shown to transform normal hematopoietic progenitors into leukemia in cooperation with Eya. However, the specific role and the underlying mechanism of Six1 in leukemia maintenance remain unexplored. Here, we showed increased expression of SIX1 in AML patients and murine leukemia stem cells (c‐Kit+ cells, LSCs). Importantly, we also observed that a higher level of Six1 in human patients predicts a worse prognosis. Notably, knockdown of Six1 significantly prolonged the survival of MLL‐AF9‐induced AML mice with reduced peripheral infiltration and tumor burden. AML cells from Six1‐knockdown (KD) mice displayed a significantly decreased number and function of LSC, as assessed by the immunophenotype, colony‐forming ability and limiting dilution assay. Further analysis revealed the augmented apoptosis of LSC and decreased expression of glycolytic genes in Six1 KD mice. Overall, our data showed that Six1 is essential for the progression of MLL‐AF9‐induced AML via maintaining the pool of LSC.

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Section: Discussionsupporting

confidence: 54%

Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia

Chu

Chen

et al. 2019

Cancer Science

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“…Ras pathway activation has been demonstrated in WT. However, until recently, it was presumed to be secondary to upstream up-regulation of the IGF2 axis or mutations in genes such as SIX1/2, DGCR8, or DROSHA (Hu et al, 2011;Walz et al, 2015). These older studies failed to identify mutations in Ras family members using single-strand conformation polymorphism analysis and direct DNA sequence analysis (Waber et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Functional KRAS mutations and a potential role for PI3K/AKT activation in Wilms tumors

et al. 2017

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Wilms tumor (WT) is the most common renal neoplasm of childhood and affects 1 in 10 000 children aged less than 15 years. These embryonal tumors are thought to arise from primitive nephrogenic rests that derive from the metanephric mesenchyme during kidney development and are characterized partly by increased Wnt/β‐catenin signaling. We previously showed that coordinate activation of Ras and β‐catenin accelerates the growth and metastatic progression of a murine WT model. Here, we show that activating KRAS mutations can be found in human WT. In addition, high levels of phosphorylated AKT are present in the majority of WT. We further show in a mouse model and in renal epithelial cells that Ras cooperates with β‐catenin to drive metastatic disease progression and promotes in vitro tumor cell growth, migration, and colony formation in soft agar. Cellular transformation and metastatic disease progression of WT cells are in part dependent on PI3K/AKT activation and are inhibited via pharmacological inhibition of this pathway. Our studies suggest both KRAS mutations and AKT activation are present in WT and may represent novel therapeutic targets for this disease.

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“…An important focus of future studies would be to address how these alterations interact with more recently identified oncogenic drivers of Wilms tumorigenesis. 15,16 If our findings can be verified in additional cases with inborn WT1 alterations, the unique 11p breakpoint of each tumor could be useful as a clinical lineage marker in patients with multifocal tumor to score the actual number of lesions and to trace the origin of metastases.…”

Section: Discussionmentioning

confidence: 73%

Convergent evolution of 11p allelic loss in multifocal Wilms tumors arising in WT1 mutation carriers

Valind

Wessman

Pal

et al. 2018

Pediatric Blood & Cancer

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Wilms tumors in patients with constitutional WT1 mutations are examples of Knudson's tumor suppressor paradigm, with somatic inactivation of the second allele occurring through 11p loss of heterozygosity. The time point of this second hit has remained unknown. We analyzed seven Wilms tumors from two patients with constitutional WT1 mutations by whole exome sequencing and genomic array. All tumors exhibited wild type WT1 loss through uniparental isodisomy. Each tumor had a unique genomic breakpoint in 11p, typically accompanied by a private activating mutation of CTNNB1. Hence, convergent evolution rather than field carcinogenesis underlies multifocal tumors in WT1 mutation carriers.

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Recurrent DGCR8, DROSHA, and SIX Homeodomain Mutations in Favorable Histology Wilms Tumors

Cited by 49 publications

References 0 publications

Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia

Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia

Functional KRAS mutations and a potential role for PI3K/AKT activation in Wilms tumors

Convergent evolution of 11p allelic loss in multifocal Wilms tumors arising in WT1 mutation carriers

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