Coexistence of LMPP-like and GMP-like Leukemia Stem Cells in Acute Myeloid Leukemia

Goardon, Nicolas; Marchi, Emanuele; Atzberger, Ann; Quek, Lynn; Schuh, Anna; Soneji, Shamit; Woll, Petter S.; Mead, Adam J.; Alford, Kate; Rout, R; Chaudhury, Salma; Gilkes, Amanda F.; Knapper, Steven; Beldjord, Kheïra; Begum, Suriya; Rose, S. Melfi; Geddes, Nicola; Griffiths, Mike; Standen, Graham R.; Sternberg, Alexander; Cavenagh, Jamie; Hunter, Hannah; Bowen, David; Killick, Sally; Robinson, L. G.; Price, Andrew; Macintyre, Elizabeth; Virgo, Paul; Burnett, Alan Kenneth; Craddock, Charles; Enver, Tariq; Jacobsen, Sten Eirik W.; Porcher, Catherine; Vyas, Paresh

doi:10.1016/j.ccr.2010.12.012

Cited by 572 publications

(649 citation statements)

References 44 publications

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“…Whereas MDS has been shown to originate from the earliest haematopoietic stem cell (Lin‐CD34 + CD38 − CD90 + ) (Woll et al , 2014), recent evidence suggest the majority of AML cases to propagate from more mature progenitors (Mora‐Jensen et al , 2015). Furthermore, in AML more than one LSC population can co‐exist in the same patient and be hierarchically ordered (Goardon et al , 2011). Speculatively, in MDS, CD34 + CD38 − CLEC12A + cells could be a distinct CSC population downstream in a CSC hierarchy.…”

Section: Discussionmentioning

confidence: 99%

Unravelling the relevance of CLEC12A as a cancer stem cell marker in myelodysplastic syndrome

et al. 2016

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SummaryEvidence of distinct disease propagating stem cells in myelodysplastic syndrome (MDS) has emerged in recent years. However, immunophenotypic characterization of these cancer stem cells remains sparse. In acute myeloid leukaemia (AML), we have previously described aberrant expression of the C‐type lectin domain family 12, member A (CLEC12A) as a stable and reliable marker of leukaemia blasts and as a tool for assessing minimal residual disease. Furthermore, CLEC12A has been proposed as a promising marker of leukaemic stem cells in AML. The role of CLEC12A in MDS, however, remains to be elucidated. In this study, we found CLEC12A aberrantly expressed on the CD34+ CD38− cell compartment in 71% (22/31) of MDS patients, distributed across all Revised International Prognostic Scoring System risk groups. We showed that the CD34+ CD38− CLEC12A+ cells were indeed malignant and possessed functional stem cell properties in the long‐term colony‐initiating cell assay. As opposed to reported findings in AML, we showed that cancer stem cells from MDS samples derived from both CLEC12A positive and negative CD34+ CD38− subpopulations. Due to the absence of CLEC12A on normal haematopoietic stem cells, CLEC12A stem cell immunophenotyping may contribute to diagnosing and monitoring MDS patients and could furthermore add knowledge about disease propagating cells in MDS.

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Section: Discussionmentioning

confidence: 99%

Unravelling the relevance of CLEC12A as a cancer stem cell marker in myelodysplastic syndrome

et al. 2016

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“…This study showed that GMPs and lymphoid-primed MPPs both had leukemia-initiating potential and that these populations are organized in a hierarchical order. 44 Our murine AML model is perfectly suited to test the effects of chemotherapy and tyrosine kinase inhibitors blocking FLT3 ITD function on specific cellular populations to investigate their specific role in relapse of leukemia after complete remission. …”

Section: Discussionmentioning

confidence: 99%

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

et al. 2012

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Biallelic CEBPA mutations and FMS-like tyrosine kinase receptor 3 (FLT3) length mutations are frequently identified in human acute myeloid leukemia (AML) with normal cytogenetics. However, the molecular and cellular mechanisms of oncogene cooperation remain unclear because of a lack of disease models. We have generated an AML mouse model using knockin mouse strains to study cooperation of an internal tandem duplication (ITD) mutation in the Flt3 gene with commonly observed CCAAT/enhancer binding protein alpha (C/EBPa) mutations. This study provides evidence that FLT3 ITD cooperates in leukemogenesis by enhancing the generation of leukemia-initiating granulocyte-monocyte progenitors (GMPs) otherwise prevented by a block in differentiation and skewed lineage priming induced by biallelic C/EBPa mutations. These cellular changes are accompanied by an upregulation of hematopoietic stem cell and STAT5 target genes. By gene expression analysis in premalignant populations, we further show a role of FLT3 ITD in activating genes involved in survival/transformation and chemoresistance. Both multipotent progenitors and GMP cells contain the potential to induce AML similar to corresponding cells in human AML samples showing that this model resembles human disease.

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“…Nevertheless, a hierarchy of cells can still be found to exist within these leukaemias 40 . In addition, perturbations of differentiation that affect normal lineage restriction processes (for example, as found in biphenotypic leukaemias), or the production of abnormal phenotypes, are well documented consequences of leukaemogenesis 41 .…”

Section: When a Clonal Hierarchy Is In Questionmentioning

confidence: 99%

Cancer stem cell definitions and terminology: the devil is in the details

Valent

Bonnet

Maria³

et al. 2012

Nat Rev Cancer

625

564

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| The cancer stem cell (CSC) concept has important therapeutic implications, but its investigation has been hampered both by a lack of consistency in the terms used for these cells and by how they are defined. Evidence of their heterogeneous origins, frequencies and their genomic, as well as their phenotypic and functional, properties has added to the confusion and has fuelled new ideas and controversies. Participants in The Year 2011 Working Conference on CSCs met to review these issues and to propose a conceptual and practical framework for CSC terminology. More precise reporting of the parameters that are used to identify CSCs and to attribute responses to them is also recommended as key to accelerating an understanding of their biology and developing more effective methods for their eradication in patients. PERSPECTIVES NATURE REVIEWS | CANCER VOLUME 12 | NOVEMBER 2012 | 767

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Coexistence of LMPP-like and GMP-like Leukemia Stem Cells in Acute Myeloid Leukemia

Cited by 572 publications

References 44 publications

Unravelling the relevance of CLEC12A as a cancer stem cell marker in myelodysplastic syndrome

Unravelling the relevance of CLEC12A as a cancer stem cell marker in myelodysplastic syndrome

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

Cancer stem cell definitions and terminology: the devil is in the details

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