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, Stephen; Karimi, Mohsen; Scharenberg, Christian; Macaulay, Iain C.; Clark, Sally A.; 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, Lars; Campbell, Peter J.; Sandberg, Rickard; Papaemmanuil, Elli; Hellström‐Lindberg, Eva; Linnarsson, Sten; Jacobsen, Sten Eirik W.

doi:10.1016/j.ccell.2015.03.003

Cited by 63 publications

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“…This is an important feature as it suggests that BH3 mimetics are capable of targeting the MDS cell of origin likely residing within the CD34 + progenitor cell compartment. 38 Similar findings were reported in a MDS mouse model, where ABT-737 was capable of prolonging the survival of mice by targeting leukemia-initiating cells and primitive Lin − /Sca1 + /Kit + cells. 54,55 However, to accurately recapitulate the high level of clinical and molecular heterogeneity of human MDS, it is of critical importance to test the effects of BH3-mimetic compounds on a large cohort or primary patient samples.…”

Section: Discussionsupporting

confidence: 67%

“…38,43 It is therefore critical to target the stem/progenitor compartment to combat the disease. Hence, we interrogated whether ABT-737-or ABT-199-induced killing of CD34 + cells had any impact on the colony-forming capacity.…”

Section: Resultsmentioning

confidence: 99%

“…38 To differentiate between MDS-propagating cells and a more differentiated cellular subpopulation, we gated on CD34 + cells by flow cytometry, the cellular subpopulation harboring, at least in part, the MDSpropagating cells. 9,10,38,39 Of note, all samples were used directly after extraction from the BM to retain optimal survival properties and to prevent apoptosis induction by prior deep-freezing.…”

Section: Resultsmentioning

confidence: 99%

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Blockade of BCL-2 proteins efficiently induces apoptosis in progenitor cells of high-risk myelodysplastic syndromes patients

et al. 2015

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Deregulated apoptosis is an identifying feature of myelodysplastic syndromes (MDS). Whereas apoptosis is increased in the bone marrow (BM) of low-risk MDS patients, progression to high-risk MDS correlates with an acquired resistance to apoptosis and an aberrant expression of BCL-2 proteins. To overcome the acquired apoptotic resistance in high-risk MDS, we investigated the induction of apoptosis by inhibition of pro-survival BCL-2 proteins using the BCL-2/-XL/-W inhibitor ABT-737 or the BCL-2-selective inhibitor ABT-199. We characterized a cohort of 124 primary human BM samples from MDS/secondary acute myeloid leukemia (sAML) patients and 57 healthy, age-matched controls. Inhibition of anti-apoptotic BCL-2 proteins was specifically toxic for BM cells from high-risk MDS and sAML patients, whereas low-risk MDS or healthy controls remained unaffected. Notably, ABT-737 or ABT-199 treatment was capable of targeting the MDS stem/progenitor compartment in high-risk MDS/sAML samples as shown by the reduction in CD34(+) cells and the decreased colony-forming capacity. Elevated expression of MCL-1 conveyed resistance against both compounds. Protection by stromal cells only partially inhibited induction of apoptosis. Collectively, our data show that the apoptotic resistance observed in high-risk MDS/sAML cells can be overcome by the ABT-737 or ABT-199 treatment and implies that BH3 mimetics might delay disease progression in higher-risk MDS or sAML patients.

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Section: Discussionsupporting

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Blockade of BCL-2 proteins efficiently induces apoptosis in progenitor cells of high-risk myelodysplastic syndromes patients

et al. 2015

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“…Telomere length both reflects and limits the replicative history of a cell. Given that a common myeloid-lymphoid stem cell of origin of the del(5q) clone has been demonstrated [20][21][22] these results indirectly support the idea of a differentiation defect of clonal, del(5q) stem cells towards the lymphoid lineage that leads to the predominance of non-clonal lymphoid cells with normal telomere length in the peripheral blood of del(5q) MDS patients. A similar phenomenon has been observed in the clonal composition and telomere biology of peripheral blood cells from untreated patients with BCR-ABL-positive CML [7] (reviewed in [9]).…”

Section: Discussionsupporting

confidence: 53%

Telomere dynamics in patients with del (5q) MDS before and under treatment with lenalidomide

et al. 2015

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“…Finally, over the last 2 years, it has become clear that the initiating mutations in both de novo [27][28][29] AML and AML secondary to myelodysplasia (MDS) [30] occur in normal hemopoietic stem cells and that this establishes a preleukemic state. It is still unclear how commonly relapse originates not only from a founder leukemic clone or sublcone, but also from preleukemic clones.…”

Section: Functional Cellular Heterogeneity In Amlmentioning

confidence: 99%

Reprint of: Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia

Vyas

Appelbaum

Craddock

2015

Biology of Blood and Marrow Transplantation

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Allogeneic stem cell transplantation is an increasingly important treatment option in the management of adult acute myeloid leukemia (AML). The major causes of treatment failure remain disease relapse and treatment toxicity. In this review, Dr Vyas presents an overview of important recent data defining molecular factors associated with treatment failure in AML. He also identifies the emerging importance of leukemia stem cell biology in determining both response to therapy and relapse risk in AML. Dr Appelbaum discusses advances in the design and delivery of both myeloablative and reduced-intensity conditioning regimens, highlighting novel strategies with the potential to improve outcome. Dr Craddock discusses the development of both novel conditioning regimens and post-transplantation strategies aimed at reducing the risk of disease relapse.

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

Cited by 63 publications

References 0 publications

Blockade of BCL-2 proteins efficiently induces apoptosis in progenitor cells of high-risk myelodysplastic syndromes patients

Blockade of BCL-2 proteins efficiently induces apoptosis in progenitor cells of high-risk myelodysplastic syndromes patients

Telomere dynamics in patients with del (5q) MDS before and under treatment with lenalidomide

Reprint of: Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia

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