Anti-CD38 antibody–mediated clearance of human repopulating cells masks the heterogeneity of leukemia-initiating cells

Taussig, David; Miraki-Moud, Farideh; Anjos-Afonso, Fernando; Pearce, Daniel J.; Allen, Kirsty; Ridler, C; Lillington, Debra M.; Oakervee, Heather; Cavenagh, Jamie; Agrawal, Samir; Lister, T. Andrew; Gribben, John G.; Bonnet, Dominique

doi:10.1182/blood-2007-10-118331

Cited by 340 publications

(318 citation statements)

References 25 publications

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“…The isolated and transplanted fraction of phenotypic GMPs caused development of leukemia in secondary recipients, which substantiates the hypothesis that LICs include committed myeloid progenitors. 18,42,43 Moreover, leukemic MPPs could also cause AML in secondary recipients with expansion of phenotypic GMP indicating a hierarchical order of these populations in leukemogenesis. Hence, our model confirms the premise of LICs possessing proliferative potential of a committed progenitor and acquiring self-renewal potential, which otherwise is restricted to stem cells.…”

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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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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“…For example, CD34 + CD38 + AML cells, as well as CD34 + CD38 − AML cells, both frequently show CSC activity when transplanted into non-obese diabetic, severe combined immunodeficient (NOD/SCID) mice lacking a functional IL2RG chain (NSG or NOG) mice, although previously, this property seemed to be mostly restricted to the CD34 + CD38 − subset when less immunodeficient NOD/SCID mice were used as recipients 38,39 . Nevertheless, a hierarchy of cells can still be found to exist within these leukaemias 40 .…”

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

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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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“…[12][13][14][15][16][17] Studies aimed at further enrichment of leukemia-initiating cells revealed substantial heterogeneity in cell surface marker expression, [18][19][20][21][22][23] and it has been observed that leukemia-initiating cells can reside both in the CD34 þ / CD38 À and in the CD34 þ /CD38 þ fractions. 24 In our current study, AML-MNC fractions were sorted in CD34 þ and CD34 À subfractions and gene expression was compared with a large group of normal CD34 þ bone marrow (BM) cells. Thus, we were able to identify AML CD34 þ -specific gene expression profiles, which included a number of genes that could significantly predict prognosis in normal-karyotype AML independent of already established prognostic factors.…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling in the leukemic stem cell-enriched CD34+ fraction identifies target genes that predict prognosis in normal karyotype AML

et al. 2011

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In order to identify acute myeloid leukemia (AML) CD34 þ -specific gene expression profiles, mononuclear cells from AML patients (n ¼ 46) were sorted into CD34 þ and CD34 À subfractions, and genome-wide expression analysis was performed using Illumina BeadChip Arrays. AML CD34 þ and CD34 À gene expression was compared with a large group of normal CD34 þ bone marrow (BM) cells (n ¼ 31). Unsupervised hierarchical clustering analysis showed that CD34 þ AML samples belonged to a distinct cluster compared with normal BM and that in 61% of the cases the AML CD34 þ transcriptome did not cluster together with the paired CD34 À transcriptome. The top 50 of AML CD34 þ -specific genes was selected by comparing the AML CD34 þ transcriptome with the AML CD34 À and CD34 þ normal BM transcriptomes. Interestingly, for three of these genes, that is, ankyrin repeat domain 28 (ANKRD28), guanine nucleotide binding protein, alpha 15 (GNA15) and UDP-glucose pyrophosphorylase 2 (UGP2), a high transcript level was associated with a significant poorer overall survival (OS) in two independent cohorts (n ¼ 163 and n ¼ 218) of normal karyotype AML. Importantly, the prognostic value of the continuous transcript levels of ANKRD28 (OS hazard ratio (HR): 1.32, P ¼ 0.008), GNA15 (OS HR: 1.22, P ¼ 0.033) and UGP2 (OS HR: 1.86, P ¼ 0.009) was shown to be independent from the well-known risk factors FLT3-ITD, NPM1c þ and CEBPA mutation status.

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Anti-CD38 antibody–mediated clearance of human repopulating cells masks the heterogeneity of leukemia-initiating cells

Cited by 340 publications

References 25 publications

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

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

Gene expression profiling in the leukemic stem cell-enriched CD34+ fraction identifies target genes that predict prognosis in normal karyotype AML

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