Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo

Petter S. Woll; Una Kjällquist; Onima Chowdhury; Helen Doolittle; David C. Wedge; Supat Thongjuea; Rikard Erlandsson; Mtakai Ngara; Kristina Anderson; Qiaolin Deng; Adam J. Mead; Laura Stenson; Alice Giustacchini; Sara Duarte; Eleni Giannoulatou; Stephen Taylor; Mohsen Karimi; Christian Scharenberg; Teresa  Mortera-Blanco; Iain C. Macaulay; Sally-Ann Clark; Ingunn Dybedal; Dag Josefsen; Pierre Fenaux; Peter Hokland; Mette S. Holm; Mario Cazzola; Luca Malcovati; Sudhir Tauro; David Bowen; Jacqueline Boultwood; Andrea Pellagatti; John E. Pimanda; Ashwin Unnikrishnan; Paresh Vyas; Gudrun Göhring; Brigitte Schlegelberger; Magnus Tobiasson; Gunnar Kvalheim; Stefan N. Constantinescu; Claus Nerlov; Lars Nilsson; Peter J. Campbell; Rikard Sandberg; Elli Papaemmanuil; Eva Hellström-Lindberg; Sten Linnarsson; Sten Erik W. Jacobsen

doi:10.1016/j.ccr.2014.03.036

Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo

Petter S. Woll, Una Kjällquist, Onima Chowdhury, Helen Doolittle, David C. Wedge, Supat Thongjuea, Rikard Erlandsson, Mtakai Ngara, Kristina Anderson, Qiaolin Deng, Adam J. Mead, Laura Stenson, Alice Giustacchini, Sara Duarte, Eleni Giannoulatou, Stephen Taylor, Mohsen Karimi, Christian Scharenberg, Teresa Mortera-Blanco, Iain C. MacaulaySally-Ann Clark, Ingunn Dybedal, Dag Josefsen, Pierre Fenaux, Peter Hokland, Mette S. Holm, Mario Cazzola, Luca Malcovati, Sudhir Tauro, David Bowen, Jacqueline Boultwood, Andrea Pellagatti, John E. Pimanda, Ashwin Unnikrishnan, Paresh Vyas, Gudrun Göhring, Brigitte Schlegelberger, Magnus Tobiasson, Gunnar Kvalheim, Stefan N. Constantinescu, Claus Nerlov, Lars Nilsson, Peter J. Campbell, Rikard Sandberg, Elli Papaemmanuil, Eva Hellström-Lindberg, Sten Linnarsson, Sten Erik W. Jacobsen (Lead / Corresponding author)

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Abstract

Evidence for distinct human cancer stem cells (CSCs) remains contentious and the degree to which differentcancer cells contribute to propagating malignancies in patients remains unexplored. In low- to intermediate-risk myelodysplastic syndromes (MDS), we establish the existence of rare multipotent MDS stem cells (MDS-SCs), and their hierarchical relationship to lineage-restricted MDS progenitors. All identified somatically acquired genetic lesions were backtracked to distinct MDS-SCs, establishing their distinct MDS-propagating function invivo. In isolated del(5q)-MDS, acquisition of del(5q) preceded diverse recurrent driver mutations. Sequential analysis in del(5q)-MDS revealed genetic evolution in MDS-SCs and MDS-progenitors prior to leukemic transformation. These findings provide definitive evidence for rare human MDS-SCs invivo, with extensive implications for the targeting of the cells required and sufficient for MDS-propagation.

Original language	English
Pages (from-to)	794-808
Number of pages	15
Journal	Cancer Cell
Volume	25
Issue number	6
DOIs	https://doi.org/10.1016/j.ccr.2014.03.036
Publication status	Published - 16 Jun 2014

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Woll, P. S., Kjällquist, U., Chowdhury, O., Doolittle, H., Wedge, D. C., Thongjuea, S., Erlandsson, R., Ngara, M., Anderson, K., Deng, Q., Mead, A. J., Stenson, L., Giustacchini, A., Duarte, S., Giannoulatou, E., Taylor, S., Karimi, M., Scharenberg, C., Mortera-Blanco, T., ... Jacobsen, S. E. W. (2014). Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo. Cancer Cell, 25(6), 794-808. https://doi.org/10.1016/j.ccr.2014.03.036

@article{e8b72e35d2274f0db7125047afa1ad49,

title = "Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo",

abstract = "Evidence for distinct human cancer stem cells (CSCs) remains contentious and the degree to which differentcancer cells contribute to propagating malignancies in patients remains unexplored. In low- to intermediate-risk myelodysplastic syndromes (MDS), we establish the existence of rare multipotent MDS stem cells (MDS-SCs), and their hierarchical relationship to lineage-restricted MDS progenitors. All identified somatically acquired genetic lesions were backtracked to distinct MDS-SCs, establishing their distinct MDS-propagating function invivo. In isolated del(5q)-MDS, acquisition of del(5q) preceded diverse recurrent driver mutations. Sequential analysis in del(5q)-MDS revealed genetic evolution in MDS-SCs and MDS-progenitors prior to leukemic transformation. These findings provide definitive evidence for rare human MDS-SCs invivo, with extensive implications for the targeting of the cells required and sufficient for MDS-propagation.",

author = "Woll, {Petter S.} and Una Kj{\"a}llquist and Onima Chowdhury and Helen Doolittle and Wedge, {David C.} and Supat Thongjuea and Rikard Erlandsson and Mtakai Ngara and Kristina Anderson and Qiaolin Deng and Mead, {Adam J.} and Laura Stenson and Alice Giustacchini and Sara Duarte and Eleni Giannoulatou and Stephen Taylor and Mohsen Karimi and Christian Scharenberg and Teresa Mortera-Blanco and Macaulay, {Iain C.} and Sally-Ann Clark and Ingunn Dybedal and Dag Josefsen and Pierre Fenaux and Peter Hokland and Holm, {Mette S.} and Mario Cazzola and Luca Malcovati and Sudhir Tauro and David Bowen and Jacqueline Boultwood and Andrea Pellagatti and Pimanda, {John E.} and Ashwin Unnikrishnan and Paresh Vyas and Gudrun G{\"o}hring and Brigitte Schlegelberger and Magnus Tobiasson and Gunnar Kvalheim and Constantinescu, {Stefan N.} and Claus Nerlov and Lars Nilsson and Campbell, {Peter J.} and Rikard Sandberg and Elli Papaemmanuil and Eva Hellstr{\"o}m-Lindberg and Sten Linnarsson and Jacobsen, {Sten Erik W.}",

year = "2014",

month = jun,

day = "16",

doi = "10.1016/j.ccr.2014.03.036",

language = "English",

volume = "25",

pages = "794--808",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Elsevier",

number = "6",

}

Woll, PS, Kjällquist, U, Chowdhury, O, Doolittle, H, Wedge, DC, Thongjuea, S, Erlandsson, R, Ngara, M, Anderson, K, Deng, Q, Mead, AJ, Stenson, L, Giustacchini, A, Duarte, S, Giannoulatou, E, Taylor, S, Karimi, M, Scharenberg, C, Mortera-Blanco, T, Macaulay, IC, Clark, S-A, Dybedal, I, Josefsen, D, Fenaux, P, Hokland, P, Holm, MS, Cazzola, M, Malcovati, L, Tauro, S, Bowen, D, Boultwood, J, Pellagatti, A, Pimanda, JE, Unnikrishnan, A, Vyas, P, Göhring, G, Schlegelberger, B, Tobiasson, M, Kvalheim, G, Constantinescu, SN, Nerlov, C, Nilsson, L, Campbell, PJ, Sandberg, R, Papaemmanuil, E, Hellström-Lindberg, E, Linnarsson, S & Jacobsen, SEW 2014, 'Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo', Cancer Cell, vol. 25, no. 6, pp. 794-808. https://doi.org/10.1016/j.ccr.2014.03.036

TY - JOUR

T1 - Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo

AU - Woll, Petter S.

AU - Kjällquist, Una

AU - Chowdhury, Onima

AU - Doolittle, Helen

AU - Wedge, David C.

AU - Thongjuea, Supat

AU - Erlandsson, Rikard

AU - Ngara, Mtakai

AU - Anderson, Kristina

AU - Deng, Qiaolin

AU - Mead, Adam J.

AU - Stenson, Laura

AU - Giustacchini, Alice

AU - Duarte, Sara

AU - Giannoulatou, Eleni

AU - Taylor, Stephen

AU - Karimi, Mohsen

AU - Scharenberg, Christian

AU - Mortera-Blanco, Teresa

AU - Macaulay, Iain C.

AU - Clark, Sally-Ann

AU - Dybedal, Ingunn

AU - Josefsen, Dag

AU - Fenaux, Pierre

AU - Hokland, Peter

AU - Holm, Mette S.

AU - Cazzola, Mario

AU - Malcovati, Luca

AU - Tauro, Sudhir

AU - Bowen, David

AU - Boultwood, Jacqueline

AU - Pellagatti, Andrea

AU - Pimanda, John E.

AU - Unnikrishnan, Ashwin

AU - Vyas, Paresh

AU - Göhring, Gudrun

AU - Schlegelberger, Brigitte

AU - Tobiasson, Magnus

AU - Kvalheim, Gunnar

AU - Constantinescu, Stefan N.

AU - Nerlov, Claus

AU - Nilsson, Lars

AU - Campbell, Peter J.

AU - Sandberg, Rikard

AU - Papaemmanuil, Elli

AU - Hellström-Lindberg, Eva

AU - Linnarsson, Sten

AU - Jacobsen, Sten Erik W.

PY - 2014/6/16

Y1 - 2014/6/16

N2 - Evidence for distinct human cancer stem cells (CSCs) remains contentious and the degree to which differentcancer cells contribute to propagating malignancies in patients remains unexplored. In low- to intermediate-risk myelodysplastic syndromes (MDS), we establish the existence of rare multipotent MDS stem cells (MDS-SCs), and their hierarchical relationship to lineage-restricted MDS progenitors. All identified somatically acquired genetic lesions were backtracked to distinct MDS-SCs, establishing their distinct MDS-propagating function invivo. In isolated del(5q)-MDS, acquisition of del(5q) preceded diverse recurrent driver mutations. Sequential analysis in del(5q)-MDS revealed genetic evolution in MDS-SCs and MDS-progenitors prior to leukemic transformation. These findings provide definitive evidence for rare human MDS-SCs invivo, with extensive implications for the targeting of the cells required and sufficient for MDS-propagation.

AB - Evidence for distinct human cancer stem cells (CSCs) remains contentious and the degree to which differentcancer cells contribute to propagating malignancies in patients remains unexplored. In low- to intermediate-risk myelodysplastic syndromes (MDS), we establish the existence of rare multipotent MDS stem cells (MDS-SCs), and their hierarchical relationship to lineage-restricted MDS progenitors. All identified somatically acquired genetic lesions were backtracked to distinct MDS-SCs, establishing their distinct MDS-propagating function invivo. In isolated del(5q)-MDS, acquisition of del(5q) preceded diverse recurrent driver mutations. Sequential analysis in del(5q)-MDS revealed genetic evolution in MDS-SCs and MDS-progenitors prior to leukemic transformation. These findings provide definitive evidence for rare human MDS-SCs invivo, with extensive implications for the targeting of the cells required and sufficient for MDS-propagation.

UR - http://www.scopus.com/inward/record.url?scp=84900360350&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2014.03.036

DO - 10.1016/j.ccr.2014.03.036

M3 - Article

C2 - 24835589

AN - SCOPUS:84902480315

SN - 1535-6108

VL - 25

SP - 794

EP - 808

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo

Abstract

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