Myelodysplastic Syndromes Are Propagated by Rare and Distinct Human Cancer Stem Cells In Vivo

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

doi:10.1016/j.ccr.2014.05.027

Cited by 39 publications

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“…1,2,8,9,20,41 It has been shown that leukemia-initiating cells can reside in different phenotypic stem and progenitor compartments at relatively low frequencies and are associated with transcription factor alterations that result in pathogenic transcriptional changes. [2][3][4][5][6][7][11][12][13]32,[42][43][44] Thus, to uncover newer stem cell-directed targets, we conducted a transcriptomic analysis on rigorously defined stem and progenitor populations in AML and MDS in comparison with their respective healthy counterparts. With this approach, we were able to identify IL8 as one of the few genes most significantly overexpressed across different stem and progenitor subsets in AML and MDS patients, indicating it might play a crucial role in the pathogenesis of AML and MDS.…”

Section: Discussionmentioning

confidence: 99%

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IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells

Schinke

Giricz

et al. 2015

Blood

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Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4][5][6][7][8][9] Despite the use of poly-chemotherapy and the development of newer agents, clinical outcome remains poor. The disease course is frequently characterized by relapse or failure to achieve durable remission, indicating that current treatment regimens do not target the cancer-initiating cells.…”

Section: Introductionmentioning

confidence: 99%

IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells

Schinke

Giricz

et al. 2015

Blood

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159

141

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“…Similar scenarios where mutations were acquired in the mature compartments have also been reported in a recent study by Woll et al 1 One of the limitations of our sequencing analysis is that any mutation present at <2% mutant allele burden (MAB) will not have been detected. Thus, we could not exclude the possibility that ASXL1 and ANGPTL5 gene mutations were acquired in the HSC fraction, but remained at low level (below our detection level) until the cells reached the MPP stage and expanded.…”

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confidence: 85%

Myelodysplastic syndrome can propagate from the multipotent progenitor compartment

et al. 2016

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“…[1][2][3] Despite their genetic heterogeneity, they share common phenotypic features including low peripheral blood counts (cytopenias) in spite of a hypercellular bone marrow (ineffective hematopoiesis), dysplasia and a variable propensity for transformation to acute myeloid leukemia (AML). 4 Programmed cell death or apoptosis of white blood cells is a common feature, and is thought to contribute to the cytopenias particularly in early stages of the disease.…”

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PUMA promotes apoptosis of hematopoietic progenitors driving leukemic progression in a mouse model of myelodysplasia

et al. 2016

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Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis with resultant cytopenias. Increased apoptosis and aberrantly functioning progenitors are thought to contribute to this phenotype. As is the case for other malignancies, overcoming apoptosis is believed to be important in progression toward acute myeloid leukemia (AML). Using the NUP98-HOXD13 (NHD13) transgenic mouse model of MDS, we previously reported that overexpression of the anti-apoptotic protein BCL2, blocked apoptosis and improved cytopenias, paradoxically, delaying leukemic progression. To further understand this surprising result, we examined the role of p53 and its pro-apoptotic effectors, PUMA and NOXA in NHD13 mice. The absence of p53 or PUMA but not NOXA reduced apoptosis and expanded the numbers of MDS-repopulating cells. Despite a similar effect on apoptosis and cell numbers, the absence of p53 and PUMA had diametrically opposed effects on progression to AML: absence of p53 accelerated leukemic progression, while absence of PUMA significantly delayed progression. This may be explained in part by differences in cellular responses to DNA damage. The absence of p53 led to higher levels of γ-H2AX (indicative of persistent DNA lesions) while PUMA-deficient NHD13 progenitors resolved DNA lesions in a manner comparable to wild-type cells. These results suggest that targeting PUMA may improve the cytopenias of MDS without a detrimental effect on leukemic progression thus warranting further investigation. Cell Death and Differentiation (2016) 23, 1049-1059 doi:10.1038/cdd.2015; published online 8 January 2016Myelodysplastic syndromes (MDS) are a genetically and clonally heterogeneous group of myeloid malignancies, likely arising from the hematopoietic stem cell. 1-3 Despite their genetic heterogeneity, they share common phenotypic features including low peripheral blood counts (cytopenias) in spite of a hypercellular bone marrow (ineffective hematopoiesis), dysplasia and a variable propensity for transformation to acute myeloid leukemia (AML). 4 Programmed cell death or apoptosis of white blood cells is a common feature, and is thought to contribute to the cytopenias particularly in early stages of the disease. The basis of ineffective hematopoiesis in MDS may also lie in the dysfunction of hematopoietic progenitors and their inability to support adequate bone marrow function. Apoptosis can be triggered by extrinsic factors, such as FAS ligand or TNF-α, or by cell-intrinsic factors such as ribosomal stress or increased reactive oxygen species. A cell extrinsic mechanism for apoptosis in MDS has been favored for many years; 5 however, recent evidence suggests a cell-intrinsic trigger, especially in del(5q) MDS for which there is evidence for activation of the tumor suppressor p53 by ribosomal dysfunction. 6,7 More aggressive stages of MDS have less apoptosis than earlier stages, 8 supporting the paradigm that acquired resistance to apoptosis of malignant progenitors is an important step in cancer progression. 9 Among hematological...

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Myelodysplastic Syndromes Are Propagated by Rare and Distinct Human Cancer Stem Cells In Vivo

Cited by 39 publications

References 0 publications

IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells

IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells

Myelodysplastic syndrome can propagate from the multipotent progenitor compartment

PUMA promotes apoptosis of hematopoietic progenitors driving leukemic progression in a mouse model of myelodysplasia

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