| 1. |
- Andersson, Anna, et al.
(författare)
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The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:4, s. 192-330
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Tidskriftsartikel (refereegranskat)abstract
- Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 × 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL.
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| 2. |
- Faber, Zachary J, et al.
(författare)
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The genomic landscape of core-binding factor acute myeloid leukemias
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 48, s. 1551-1556
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Tidskriftsartikel (refereegranskat)abstract
- Acute myeloid leukemia (AML) comprises a heterogeneous group of leukemias frequently defined by recurrent cytogenetic abnormalities, including rearrangements involving the core-binding factor (CBF) transcriptional complex. To better understand the genomic landscape of CBF-AMLs, we analyzed both pediatric (n = 87) and adult (n = 78) samples, including cases with RUNX1-RUNX1T1 (n = 85) or CBFB-MYH11 (n = 80) rearrangements, by whole-genome or whole-exome sequencing. In addition to known mutations in the Ras pathway, we identified recurrent stabilizing mutations in CCND2, suggesting a previously unappreciated cooperating pathway in CBF-AML. Outside of signaling alterations, RUNX1-RUNX1T1 and CBFB-MYH11 AMLs demonstrated remarkably different spectra of cooperating mutations, as RUNX1-RUNX1T1 cases harbored recurrent mutations in DHX15 and ZBTB7A, as well as an enrichment of mutations in epigenetic regulators, including ASXL2 and the cohesin complex. This detailed analysis provides insights into the pathogenesis and development of CBF-AML, while highlighting dramatic differences in the landscapes of cooperating mutations for these related AML subtypes.
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| 3. |
- Salmén, Fredrik, 1984-
(författare)
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Spatially resolved and single cell transcriptomics
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In recent years, massive parallel sequencing has revolutionized the field of biology and has provided us with a vast number of new discoveries in fields such as neurology, developmental biology and cancer research. A significant area is deciphering gene expression patterns, as well as other aspects of transcriptome information, such as the impact of splice variants and mutations on biological functions and disease development. By applying RNA-sequencing, one can extract this type of information in a large-scale manner. The most recent approaches include high-resolution techniques such as single cell sequencing and in situ methods in order to circumvent the problems with gene expression averaging in homogenized samples, and loss of spatial information.The research in this thesis is focused on the development of a novel genome-wide spatial transcriptomics method. The technique is used for analysis of intact tissue sections as well as single cells from solution, with the aim to combine gene expression and morphological information. In Paper I, the method is described in detail, and it is shown that the method is able to generate spatial high quality data from mouse olfactory bulb tissue sections (a part of the forebrain) as well as from tissue sections from breast cancer samples. In Paper III, we adapt the library preparation method in order to be able to execute it on a robotic workstation, thus increasing the reproducibility and the throughput, and decreasing the hands-on time. In Paper IV, we generate 3D-data from breast cancer samples by serial sectioning. We show that the gene expression can be highly variable along all three axes of a tumor, and we track pathways with specific spatial activity, as well as perform subtype classification with three-dimensional resolution. In Paper II, we present a high-throughput method for single cell transcriptomics of cells in solution. The method is based on the same type of solid surface capture as the tissue protocol described in Papers I, III and IV. Again, we show that we can generate high-quality gene expression data, and connect this to morphological characteristics of the analyzed single cells; both using cultured cells and samples from patients with leukemia.
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