Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2Rγc-deficient mice

Sarry, Jean-Emmanuel; Murphy, Kathleen M.; Perry, Robin; Sanchez, Patricia Vanessa; Secreto, Anthony; Keefer, Cathy; Swider, Cezary; Strzelecki, Anne-Claire; Cavelier, Cindy; Récher, Christian; Mas, Véronique Mansat‐De; Delabesse, Éric; Danet-Desnoyers, Gwenn; Carroll, Martin

doi:10.1172/jci41495

Cited by 349 publications

(340 citation statements)

References 32 publications

Supporting

Mentioning

309

Contrasting

Unclassified

Order By: Relevance

“…Recently, there have been increasing efforts to identify molecular aberrations that could serve as pharmacologic targets within AML and MDS stem cell compartments. [10][11][12][13][14][15][16] Resulting therapies have shown promising effects in preclinical studies, 17,18 but further work will be necessary to identify therapeutic targets against preleukemic stem cells that would lead to long-term remission and prevention of relapse in AML and MDS.…”

Section: Introductionmentioning

confidence: 99%

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

Schinke

Giricz

et al. 2015

Blood

158

141

View full text Add to dashboard Cite

show abstract

Section: Introductionmentioning

confidence: 99%

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

Schinke

Giricz

et al. 2015

Blood

158

141

View full text Add to dashboard Cite

show abstract

“…2 Previous studies have clearly established the biological heterogeneity of AML as well as sophisticated experimental systems to evaluate the efficacy of candidate regimens (5)(6)(7)(8). Furthermore, among human tumors, AML has arguably the best-characterized cancer stem cell population.…”

mentioning

confidence: 99%

Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

Pei¹,

Minhajuddin²,

D’Alessandro

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Although multidrug approaches to cancer therapy are common, few strategies are based on rigorous scientific principles. Rather, drug combinations are largely dictated by empirical or clinical parameters. In the present study we developed a strategy for rational design of a regimen that selectively targets human acute myelogenous leukemia (AML) stem cells. As a starting point, we used parthenolide, an agent shown to target critical mechanisms of redox balance in primary AML cells. Next, using proteomic, genomic, and metabolomic methods, we determined that treatment with parthenolide leads to induction of compensatory mechanisms that include up-regulated NADPH production via the pentose phosphate pathway as well as activation of the Nrf2-mediated oxidative stress response pathway. Using this knowledge we identified 2-deoxyglucose and temsirolimus as agents that can be added to a parthenolide regimen as a means to inhibit such compensatory events and thereby further enhance eradication of AML cells. We demonstrate that the parthenolide, 2-deoxyglucose, temsirolimus (termed PDT) regimen is a potent means of targeting AML stem cells but has little to no effect on normal stem cells. Taken together our findings illustrate a comprehensive approach to designing combination anticancer drug regimens.Numerous studies have documented the biological complexity of human tumor cell populations in which genetic, epigenetic, biochemical, and metabolic properties can often be quite heterogeneous (1, 2). As a result, complicated multidrug regimens are often employed to target various components of tumor biology and/or acquired drug resistance (3, 4). However, the rationale behind the design of multidrug regimens is usually inconsistent and often driven by pragmatism more than scientific rigor. Thus, establishing more effective means by which to identify optimal drug regimens is an important priority, particularly with the recent emergence of a broad range of targeted agents.

show abstract

“…Recent xenotransplantation studies in NSG mice confirmed the rarity of LSCs (~1 per 0.15-4.1 × 10 6 ), but revealed more unexpected heterogeneity of SCID leukemia-initiating cells, which were found not only in Lin -CD38 -fraction but also in CD34 -, Lin + , CD38 + , and CD45RA + fractions [115]. Importantly, the new study [115] indicates that the AML LSCs do not necessarily derive from the normal HSCs as initially hypothesized [112,113], emphasizing the potential disconnect between CSCs and normal stem cells.…”

Section: Csc Heterogeneitymentioning

confidence: 99%

“…Many examples of CSCs discussed in the preceding section in multiple tumor systems have been shown to be generally much less differentiated. For example, although LSC activity has been detected in several cellular compartments, the most tumorigenic subpopulation is still in undifferentiated Lin -CD34 + CD38 -cells, which can develop into more mature, less tumorigenic cells [112,113,115]. Likewise, in marker-independent sphere-(e.g., neurosphere, mammosphere, colonosphere, prostasphere, etc) formation assays, it has been repeatedly demonstrated that a single (undifferentiated) tumor cell can generate a sphere that contains multiple types of lineage-differentiated cells [49,61,66,76,80,90,95,100,106].…”

Section: Intrinsic and Induced Plasticity In Csc Progenymentioning

confidence: 99%

Understanding cancer stem cell heterogeneity and plasticity

2012

View full text Add to dashboard Cite

Heterogeneity is an omnipresent feature of mammalian cells in vitro and in vivo. It has been recently realized that even mouse and human embryonic stem cells under the best culture conditions are heterogeneous containing pluripotent as well as partially committed cells. Somatic stem cells in adult organs are also heterogeneous, containing many subpopulations of self-renewing cells with distinct regenerative capacity. The differentiated progeny of adult stem cells also retain significant developmental plasticity that can be induced by a wide variety of experimental approaches. Like normal stem cells, recent data suggest that cancer stem cells (CSCs) similarly display significant phenotypic and functional heterogeneity, and that the CSC progeny can manifest diverse plasticity. Here, I discuss CSC heterogeneity and plasticity in the context of tumor development and progression, and by comparing with normal stem cell development. Appreciation of cancer cell plasticity entails a revision to the earlier concept that only the tumorigenic subset in the tumor needs to be targeted. By understanding the interrelationship between CSCs and their differentiated progeny, we can hope to develop better therapeutic regimens that can prevent the emergence of tumor cell variants that are able to found a new tumor and distant metastases.

show abstract

Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2Rγc-deficient mice

Cited by 349 publications

References 32 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

Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

Understanding cancer stem cell heterogeneity and plasticity

Contact Info

Product

Resources

About