Research team Martin Enge
Cancer stem cells and clonal structure in ALL
Pediatric Acute Lymphoblastic Leukemia (ALL) arises from lymphocyte progenitors and is known to maintain a hierarchy of cell differentiation, making it a suitable model disease for studying cancer stem cells. Although cure rates for ALL are currently above 80%, the prognosis of patients with relapsed ALL is dismal, with an overall survival rate of only 30%. We are analyzing primary and relapsed ALL from the same patient, with the aim of determining the clonal structure of the leukemia and characterize the cancer stem cell population in the primary sample of patients which later relapse. To differentiate between genetic and epigenetic changes, we are using a novel method that allows us to obtain genotypic and transcriptomic data from the same single cell, allowing us to trace clonal expansions that are mainly driven by epigenetic factors as well as those driven by genetic alterations.
a) The cancer stem cell hypothesis postulates the existence of rare cells that show stem cell properties (marked CSC), and that give rise to genetically identical but phenotypically and epigenetically distinct progeny - resulting in a hierarchy mimicking the differentiation steps in healthy tissue. b) Classical model, where cancer cell characteristics are changed exclusively by a gradual accumulation of stochastic genetic events (mutation, loss/duplication/translocation). Importantly, both models can give rise to a tumor mass with similar characteristics, including fraction of cells with a certain phenotype. Obtaining transcriptomic and genotypic data in parallel is necessary to disentangle which features originate in genetic alterations (b) and which stem from epigenetic changes (a).
Department of Oncology-Pathology
Karolinska University Hospital and Institutet
S-171 76 Stockholm
- KAW (Stanford link)
- Magnus Bergvall
- Felix Mindus
- Junior Grant, Strategic Research Area Stem Cells and Regenerative Medicine
For full publication list, see google scholar
Single-Cell Analysis of Human Pancreas Reveals Transcriptional Signatures of Aging and Somatic Mutation Patterns.
Enge M, Arda H, Mignardi M, Beausang J, Bottino R, Kim S, et al
Cell 2017 Oct;171(2):321-330.e14
Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx.
Chakravarthy H, Gu X, Enge M, Dai X, Wang Y, Damond N, et al
Cell Metab. 2017 03;25(3):622-634
DNA-dependent formation of transcription factor pairs alters their binding specificity.
Jolma A, Yin Y, Nitta K, Dave K, Popov A, Taipale M, et al
Nature 2015 Nov;527(7578):384-8
CTCF/cohesin-binding sites are frequently mutated in cancer.
Katainen R, Dave K, Pitkänen E, Palin K, Kivioja T, Välimäki N, et al
Nat. Genet. 2015 Jul;47(7):818-21
A survey of human brain transcriptome diversity at the single cell level.
Darmanis S, Sloan S, Zhang Y, Enge M, Caneda C, Shuer L, et al
Proc. Natl. Acad. Sci. U.S.A. 2015 Jun;112(23):7285-90
Transcription factor binding in human cells occurs in dense clusters formed around cohesin anchor sites.
Yan J, Enge M, Whitington T, Dave K, Liu J, Sur I, et al
Cell 2013 Aug;154(4):801-13
DNA-binding specificities of human transcription factors.
Jolma A, Yan J, Whitington T, Toivonen J, Nitta K, Rastas P, et al
Cell 2013 Jan;152(1-2):327-39
Mice lacking a Myc enhancer that includes human SNP rs6983267 are resistant to intestinal tumors.
Sur I, Hallikas O, Vähärautio A, Yan J, Turunen M, Enge M, et al
Science 2012 Dec;338(6112):1360-3
Counting absolute numbers of molecules using unique molecular identifiers.
Kivioja T, Vähärautio A, Karlsson K, Bonke M, Enge M, Linnarsson S, et al
Nat. Methods 2011 Nov;9(1):72-4
MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas.
Mäkinen N, Mehine M, Tolvanen J, Kaasinen E, Li Y, Lehtonen H, et al
Science 2011 Oct;334(6053):252-5
MDM2-dependent downregulation of p21 and hnRNP K provides a switch between apoptosis and growth arrest induced by pharmacologically activated p53.
Enge M, Bao W, Hedström E, Jackson S, Moumen A, Selivanova G
Cancer Cell 2009 Mar;15(3):171-83