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  • 1
    Publication Date: 2013-11-15
    Description: Introduction Mixed Lineage Leukemia-negative (MLL-) infant leukemia (IL) is an extremely rare, sporadic, and often fatal form of leukemia in children less than one year of age with overall survival
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 2
    Publication Date: 2014-12-06
    Description: Introduction: Infant Leukemia (IL) has a grim prognosis; fewer than half of cases survive, and survivors are often left with lifelong deficits in cognitive and other development as a result of treatment (Chow, Friedman, & Yasui, 2007; Linabery & Ross, 2008). Rearrangements in the Mixed Lineage Leukemia (MLL+) gene are frequent in IL (Ross, Davies, Potter, & Robison, 1994; Sam et al., 2012), but, on their own, are not sufficient to induce short-latency leukemia (Montes et al., 2011). Tumor sequencing studies have demonstrated that there are very few somatic mutations present in these malignancies (Andersson et al., 2012), suggesting that there are other factors contributing to IL pathogenesis. To explore the possible contribution of rare, germline variation to early leukemogenesis, we previously completed germline exome sequencing of infants with leukemia and their mothers using samples collected by the Children’s Oncology Group. We showed that infants with wild-type MLL are born with an enrichment of rare, non-synonymous, deleterious variation in genes that were previously and independently shown to frequently harbor somatic mutations in leukemia (Valentine et al., 2013). This work is a complementary analysis of newly completed MLL+ IL germline exome sequencing. Methods: We performed germline exome sequencing on 14 mother-infant pairs with MLL+ IL and 25 unaffected children. Variants were filtered as previously described (Valentine et al., 2013), and lists of 655 AML- and 125 ALL-related genes were obtained from COSMIC (http://www.sanger.ac.uk/genetics/CGP /cosmic). All frequently occurring variants in MLL3 were validated by Sanger sequencing. Results: Like MLL-cases, MLL+ IL cases had a significant enrichment of rare, non-synonymous germline variation in leukemia-associated genes, relative to controls (Fisher’s Exact: p=0.002 for ALL, p=1.29E-10 for AML). A randomization test controlling for bias due to gene size or mutational heterogeneity in the candidate gene list remained highly significant (99.4 percentile for ALL and 〉99.99 percentile for AML). Independent of MLL status, there is a high prevalence of germline compound heterozygosity for rare, non-synonymous, deleterious variants in MLL3 (100% in infants with AML, ~60% in infants with ALL). Further, the variation clustered 5’ to MLL3’s two RING domains, important for recognizing H2A- and H2B-specific ubiquitylation and modulating the enzyme’s methyltransferase activity (Vethantham et al., 2012; Wu, Lee, Zhou, Nguyen, & Muir, 2013). This pattern of germline MLL3 variation was validated in an independent cohort undergoing whole genome sequencing (Andersson et al., 2012). Discussion: There is mounting evidence that inherited germline variation plays an important role in IL. MLL3, a homolog of MLL, is important for developmental regulation of HOX genes and mesoderm (Bhagwat & Vakoc, 2014). Further, MLL3 was recently shown to act as a tumor suppressor in adult AML (Chen et al., 2014), and is among the most frequently mutated genes across all human cancers (Lawrence et al., 2014). Our observation of deleterious germline compound heterozygosity in MLL3 suggests that dysfunction of this gene may result in epigenetic dysregulation during hematopoietic differentiation, which could contribute to the in utero development of leukemia in these infants. Further studies to characterize the role of MLL3 in hematopoiesis and leukemogenesis are underway. Disclosures No relevant conflicts of interest to declare.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 3
    Publication Date: 2016-12-02
    Description: The generation of hematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) is a major goal for regenerative medicine, as it will provide an unlimited source of these cells for transplantation, and a unique platform for the study of both normal and disease hematopoietic processes. To reproducibly achieve this goal in all hPSC lines, we must first fully understand hematopoietic ontogeny. Understanding hematopoietic development is complicated by the existence of at least two distinct programs during development that are difficult to distinguish: a transient "primitive" extra-embryonic hematopoietic program that does not give rise to HSCs, and a "definitive" program that gives rise to HSCs and all hematopoietic lineages. We have recently developed a novel method to obtain and identify, from hPSCs, mesoderm harboring exclusively primitive or exclusively definitive hematopoietic potential, by the differential expression of CD235a within KDR+ mesoderm. With this, we were able to determine that stage-specific canonical Wnt signaling specified the definitive hematopoietic program, while simultaneously repressing the primitive hematopoietic program. Further, we have now found that definitive hematopoietic specification is also dependent on bFGF signaling during this same window of time. We then asked if this tractable system could help us understand the genetic regulation of definitive hematopoietic specification from hPSCs. We isolated Wnt-dependent KDR+CD235a- definitive hematopoietic mesoderm and Wnt-independent KDR+CD235a+ primitive hematopoietic mesoderm and performed whole-transcriptome gene expression analysis, which revealed strong CDX and HOX gene enrichment exclusively within KDR+CD235a- definitive hematopoietic mesoderm. Monitoring CDX expression over time in the differentiation cultures revealed that both CDX1 and CDX2 were expressed in a bFGF-independent manner, prior to Wnt-dependent definitive hematopoietic KDR+CD235a- mesoderm specification. In contrast, CDX4 was expressed exclusively within definitive hematopoietic KDR+CD235a- mesoderm in a Wnt- and bFGF-dependent manner. This expression pattern suggested that CDX4 expression is specific to definitive, but not primitive, hematopoietic specification. To determine whether CDX4 expression plays a role in definitive hematopoietic specification, we generated an inducible CDX4 expression hPSC line using the "safe-harbor" AAVS1 locus. We manipulated exogenous CDX4 expression during the same stage of the differentiation culture that Wnt signaling is critical for definitive hematopoietic specification. Interestingly, in the absence of Wnt stimulation, exogenous CDX4 expression caused a 〉90% repression in primitive hematopoietic potential. Critically, CDX4 expression during this same time conferred 10-fold greater definitive hematopoietic potential within CD34+CD73-CD184- hemogenic endothelium, giving rise to definitive erythroid-myeloid-lymphoid multilineage progenitors. This is consistent with CDX4 being the transcriptional effector of Wnt signaling during early hematopoietic specification within mesoderm. We next generated a CDX4 knockout hPSC line by CRISPR/Cas9, and a CDX4 knockdown hPSC line via shRNA expression from the AAVS1 locus. As expected, the absence of CDX4 expression did not reduce primitive hematopoietic potential in comparison to control lines. However, when Wnt signaling was stimulated to specify definitive hematopoiesis, hPSCs lacking CDX4 expression exhibited a 10-fold decrease in definitive CD34+CD73-CD184- hemogenic endothelium specification, indicating its expression is critical for definitive hematopoietic specification. Taken together, these findings indicate that CDX4 is the earliest identified transcription factor that is a critical regulator of human definitive hematopoietic specification, and provide a mechanistic basis for Wnt-mediated definitive hematopoietic specification from hPSCs. By understanding the genetic regulation of early definitive hematopoietic specification from hPSCs, we can now identify the additional signal pathways required for efficient HSC specification from hPSCs. Disclosures No relevant conflicts of interest to declare.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 4
    Publication Date: 2017-06-01
    Description: Key Points CDX genes are differentially expressed in mesoderm harboring definitive hematopoietic potential in a WNT-dependent manner. CDX4 expression during mesoderm specification regulates human definitive hematopoietic specification.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 5
    Publication Date: 1974-05-01
    Print ISSN: 0022-2836
    Electronic ISSN: 1089-8638
    Topics: Biology
    Published by Elsevier
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