An insertional mutagenesis screen identifies genes that cooperate with Mll-AF9 in a murine leukemogenesis model

Bergerson, Rachel J.; Collier, Lara S.; Sarver, Aaron L.; Been, Raha A.; Lugthart, Sanne; Diers, Miechaleen D.; Zuber, Johannes; Rappaport, Amy; Nixon, Molly J; Silverstein, Kevin A.T.; Fan, Danhua; Lamblin, Anne Françoise; Wolff, Linda; Kersey, John H.; Delwel, Ruud; Lowe, Scott W.; O’Sullivan, M. Gerard; Kogan, Scott C.; Adams, David J.; Largaespada, David A.

doi:10.1182/blood-2010-04-281428

Cited by 22 publications

(15 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PIK3R5 functions as a regulator of the PI3K pathway, a major oncogenic signaling node in leukemias and many other tumor types. Corroborating the potential importance of this gene to leukemogenesis, Pik3r5 was recently identified in two in vivo insertional mutagenesis screens for genes that cooperate with Mll-AF9 and NPM1 in AML (14,22).…”

Section: Discussionmentioning

confidence: 99%

“…Transposon-mediated mutagenesis has emerged as a powerful methodology for functionally annotating cancer genomes. A number of studies have utilized transposon-based insertional mutagenesis screens in mice to identify and validate a number of genes relevant to tumorigenesis, including T-cell leukemia, hepatocellular carcinoma, medulloblastoma, and nerve sheath tumors (14)(15)(16)(17)(18)(19)(20)(21). To date, a vast majority of studies have relied upon the mobilization of mutagenic DNA transposons such as Sleeping Beauty (SB) or piggyBac in transgenic mouse models.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Comprehensive Ex Vivo Transposon Mutagenesis Identifies Genes That Promote Growth Factor Independence and Leukemogenesis

et al. 2016

View full text Add to dashboard Cite

Aberrant signaling through cytokine receptors and their downstream signaling pathways is a major oncogenic mechanism underlying hematopoietic malignancies. To better understand how these pathways become pathologically activated and to potentially identify new drivers of hematopoietic cancers, we developed a high-throughput functional screening approach using ex vivo mutagenesis with the Sleeping Beauty transposon. We analyzed over 1,100 transposon-mutagenized pools of Ba/F3 cells, an IL3-dependent pro-B-cell line, which acquired cytokine independence and tumor-forming ability. Recurrent transposon insertions could be mapped to genes in the JAK/ STAT and MAPK pathways, confirming the ability of this strategy to identify known oncogenic components of cytokine signaling pathways. In addition, recurrent insertions were identified in a large set of genes that have been found to be mutated in leukemia or associated with survival, but were not previously linked to the JAK/STAT or MAPK pathways nor shown to functionally contribute to leukemogenesis. Forced expression of these novel genes resulted in IL3-independent growth in vitro and tumorigenesis in vivo, validating this mutagenesis-based approach for identifying new genes that promote cytokine signaling and leukemogenesis. Therefore, our findings provide a broadly applicable approach for classifying functionally relevant genes in diverse malignancies and offer new insights into the impact of cytokine signaling on leukemia development.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comprehensive Ex Vivo Transposon Mutagenesis Identifies Genes That Promote Growth Factor Independence and Leukemogenesis

et al. 2016

View full text Add to dashboard Cite

show abstract

“…While most items on the checklist for taking preventive action (Text Box 2) have been completed, one notable exception is that, to date, animal studies of leukemia have been limited, since it is only recently that animal models of human childhood leukemia have been developed. 190 …”

Section: A Clinical Perspective On Environmental Health Literacymentioning

confidence: 99%

Childhood Leukemia and Primary Prevention

Whitehead

Metayer

Wiemels

et al. 2016

Current Problems in Pediatric and Adolescent Health Care

100

View full text Add to dashboard Cite

Leukemia is the most common pediatric cancer, affecting 3,800 children per year in the United States. Its annual incidence has increased over the last decades, especially among Latinos. Although most children diagnosed with leukemia are now cured, many suffer long-term complications, and primary prevention efforts are urgently needed. The early onset of leukemia – usually before age five – and the presence at birth of “pre-leukemic” genetic signatures indicate that pre- and postnatal events are critical to the development of the disease. In contrast to most pediatric cancers, there is a growing body of literature – in the United States and internationally – that has implicated several environmental, infectious, and dietary risk factors in the etiology of childhood leukemia, mainly for acute lymphoblastic leukemia, the most common subtype. For example, exposures to pesticides, tobacco smoke, solvents, and traffic emissions have consistently demonstrated positive associations with the risk of developing childhood leukemia. In contrast, intake of vitamins and folate supplementation during the pre-conception period or pregnancy, breastfeeding, and exposure to routine childhood infections have been shown to reduce the risk of childhood leukemia. Some children may be especially vulnerable to these risk factors, as demonstrated by a disproportionate burden of childhood leukemia in the Latino population of California. The evidence supporting the associations between childhood leukemia and its risk factors – including pooled analyses from around the world and systematic reviews – is strong; however, the dissemination of this knowledge to clinicians has been limited. To protect children’s health, it is prudent to initiate programs designed to alter exposure to well-established leukemia risk factors rather than to suspend judgement until no uncertainty remains. Primary prevention programs for childhood leukemia would also result in the significant co-benefits of reductions in other adverse health outcomes that are common in children, such as detriments to neurocognitive development.

show abstract

“…Over the last decade, transposon-mediated mutagenesis has emerged as a powerful method for functionally annotating cancer genomes. A large number of studies have utilized transposon-based insertional mutagenesis screens in mice to identify and validate a number of genes relevant to tumorigenesis, including T-cell leukemia, colon cancer, hepatocellular carcinoma, medulloblastoma, and nerve sheath tumors [1–8]. To date, the vast majority of studies have relied upon the mobilization of mutagenic DNA transposons such as Sleeping Beauty ( SB ) or piggyBac in transgenic mouse models.…”

Section: Introductionmentioning

confidence: 99%

Ex Vivo Transposon-Mediated Genetic Screens for Cancer Gene Discovery

O’Donnell

Guo

Suresh

et al. 2018

Methods in Molecular Biology

View full text Add to dashboard Cite

Transposon mutagenesis has emerged as a powerful methodology for functionally annotating cancer genomes. Although in vivo transposon-mediated forward genetic screens have proven to be valuable for cancer gene identification, they are also time-consuming and resource intensive. To facilitate the rapid and cost-effective identification of genes that regulate tumor promoting pathways, we developed a complementary ex vivo transposon mutagenesis approach wherein human or mouse cells growing in culture are mutagenized and screened for the acquisition of specific phenotypes in vitro or in vivo, such as growth factor independence or tumor forming ability. This approach allows discovery of both gain- and loss-of-function mutations in the same screen. Transposon insertions sites are recovered by high-throughput sequencing. We recently applied this system to comprehensively identify and validate genes that promote growth factor independence and transformation of murine Ba/F3 cells. Here we describe a method for performing ex vivo Sleeping Beauty-mediated mutagenesis screens in these cells, which may be adapted for the acquisition of many different phenotypes in distinct cell types.

show abstract

An insertional mutagenesis screen identifies genes that cooperate with Mll-AF9 in a murine leukemogenesis model

Cited by 22 publications

References 39 publications

Comprehensive Ex Vivo Transposon Mutagenesis Identifies Genes That Promote Growth Factor Independence and Leukemogenesis

Comprehensive Ex Vivo Transposon Mutagenesis Identifies Genes That Promote Growth Factor Independence and Leukemogenesis

Childhood Leukemia and Primary Prevention

Ex Vivo Transposon-Mediated Genetic Screens for Cancer Gene Discovery

Contact Info

Product

Resources

About