Genetic manipulation of primitive leukemic and normal hematopoietic cells using a novel method of adenovirus-mediated gene transfer

Howard, DS; Rizzierri, DA; Grimes, Barry; Upchurch, Donna; Gl, Phillips; Ak, Shalek; Yannelli, JR; Jordan, Craig T.

doi:10.1038/sj.leu.2401541

Cited by 22 publications

(12 citation statements)

References 39 publications

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“…+ hematopoietic progenitor cells and compared the ␤-galactosidase activity of 20 Indeed, when we combined Superfect with Ad/CMV-GFP, the fluorescent (ie infected) population of CD34 + cells reached 60% at MOI of 10 000 (data not shown). When we infected human CD34 + progenitor cells with Ad/hTERTLacZ or Ad/CMV-LacZ under similar conditions, the difference in ␤-galactosidase activity was more than 100-fold (Figure 4), which is similar to that in other normal cells (Figure 1b).…”

Section: Minimal Htert Activity In Hematopoietic Cd34mentioning

confidence: 99%

hTERT promoter induces tumor-specific Bax gene expression and cell killing in syngenic mouse tumor model and prevents systemic toxicity

Andreeff

Roth

et al. 2002

Gene Ther

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Section: Minimal Htert Activity In Hematopoietic Cd34mentioning

confidence: 99%

hTERT promoter induces tumor-specific Bax gene expression and cell killing in syngenic mouse tumor model and prevents systemic toxicity

Andreeff

Roth

et al. 2002

Gene Ther

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“…Thus, I B-SR expression exerts potent inhibition of NF-B activity as a result of stabilized I B␣ protein levels. Three primary AML specimens were transduced with the Ad-I B-SR vector (Ad-I B) or a control virus encoding GFP alone (Ad-GFP) as described (31). Infected populations then were monitored over time to assess viability of CD34 ϩ blast cells.…”

Section: Inhibition Of Nf-b Contributes To Apoptosis Induced By Mg-13mentioning

confidence: 99%

Preferential induction of apoptosis for primary human leukemic stem cells

Guzmán

Swiderski

Howard

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

392

292

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Acute myelogenous leukemia (AML) is typically a disease of stem͞ progenitor cell origin. Interestingly, the leukemic stem cell (LSC) shares many characteristics with normal hematopoietic stem cells (HSCs) including the ability to self-renew and a predominantly G 0 cell-cycle status. Thus, although conventional chemotherapy regimens often ablate actively cycling leukemic blast cells, the primitive LSC population is likely to be drug-resistant. Moreover, given the quiescent nature of LSCs, current drugs may not effectively distinguish between malignant stem cells and normal HSCs. Nonetheless, based on recent studies of LSC molecular biology, we hypothesized that certain unique properties of leukemic cells could be exploited to induce apoptosis in the LSC population while sparing normal stem cells. In this report we describe a strategy using treatment of primary AML cells with the proteasome inhibitor carbobenzoxyl-L-leucyl-L-leucyl-L-leucinal (MG-132) and the anthracycline idarubicin. Comparison of normal and leukemic specimens using in vitro culture and in vivo xenotransplantation assays shows that the combination of these two agents induces rapid and extensive apoptosis of the LSC population while leaving normal HSCs viable. Molecular genetic studies using a dominantnegative allele of inhibitor of nuclear factor B (I B␣) demonstrate that inhibition of nuclear factor B (NF-B) contributes to apoptosis induction. In addition, gene-expression analyses suggest that activation of p53-regulated genes are also involved in LSC apoptosis.Collectively, these findings demonstrate that malignant stem cells can be preferentially targeted for ablation. Further, the data begin to elucidate the molecular mechanisms that underlie LSC-specific apoptosis and suggest new directions for AML therapy.

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“…Notably, however, we and others have observed that AML cells can indeed be infected readily with adenoviral vectors, albeit with markedly variable efficiency (reported transduction efficiencies range from 0 to 83% 3 among investigators, and demonstrate marked intrastudy variability as well 3 ). The basis for this variability has not been defined.…”

Section: To the Editormentioning

confidence: 77%

Reduced expression of the coxsackievirus and adenovirus receptor and of αv integrins differentiates myelodysplasia-related and primary acute myeloid leukaemia

et al. 2004

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Genetic manipulation of primitive leukemic and normal hematopoietic cells using a novel method of adenovirus-mediated gene transfer

Cited by 22 publications

References 39 publications

hTERT promoter induces tumor-specific Bax gene expression and cell killing in syngenic mouse tumor model and prevents systemic toxicity

hTERT promoter induces tumor-specific Bax gene expression and cell killing in syngenic mouse tumor model and prevents systemic toxicity

Preferential induction of apoptosis for primary human leukemic stem cells

Reduced expression of the coxsackievirus and adenovirus receptor and of αv integrins differentiates myelodysplasia-related and primary acute myeloid leukaemia

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