Effect of histone deacetylase inhibitor valproic acid on progenitor cells of acute myeloid leukemia

Bug, Gesine; Schwarz, K.; Schoch, Claudia; Kampfmann, Manuela; Henschler, Reinhard; Hoelzer, Dieter; Ottmann, Oliver G.; Ruthardt, Martin

doi:10.3324/haematol.10758

Cited by 45 publications

(30 citation statements)

References 17 publications

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“…40,41 Similarly, VPA may enhance, in vitro, clonogenic capacity of CD34 þ AML progenitor cells. 42,43 Our findings explain the poor outcome of AML patients and even several cases of rapid disease progression in clinical studies using VPA. 23,40 Our observations again uncouple differentiation from APL eradication and have important new implications for the underlying mechanisms.…”

Section: Discussionmentioning

confidence: 66%

Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL

et al. 2012

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Aberrant histone acetylation was physiopathologically associated with the development of acute myeloid leukemias (AMLs). Reversal of histone deacetylation by histone deacetylase inhibitor (HDACis) activates a cell death program that allows tumor regression in mouse models of AMLs. We have used several models of PML-RARA-driven acute promyelocytic leukemias (APLs) to analyze the in vivo effects of valproic acid, a well-characterized HDACis. Valproic acid (VPA)-induced rapid tumor regression and sharply prolonged survival. However, discontinuation of treatment was associated to an immediate relapse. In vivo, as well as ex vivo, VPA-induced terminal granulocytic differentiation. Yet, despite full differentiation, leukemia-initiating cell (LIC) activity was actually enhanced by VPA treatment. In contrast to all-trans retinoic acid (ATRA) or arsenic, VPA did not degrade PML-RARA. However, in combination with ATRA, VPA synergized for PML-RARA degradation and LIC eradication in vivo. Our studies indicate that VPA triggers differentiation, but spares LIC activity, further uncouple differentiation from APL clearance and stress the importance of PML-RARA degradation in APL cure.

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Section: Discussionmentioning

confidence: 66%

Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL

et al. 2012

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“…Our results suggest that this principle may also be true for primitive FLT3-ITD þ progenitors from AML. This counterproductive effect on leukemic stem/progenitor cells has also been reported for other novel treatment strategies in AML, such as the histone deacetylase inhibitor valproate (39).…”

Section: Discussionmentioning

confidence: 91%

Stromal Niche Cells Protect Early Leukemic FLT3-ITD+ Progenitor Cells against First-Generation FLT3 Tyrosine Kinase Inhibitors

et al. 2011

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Targeting constitutively activated FMS-like tyrosine kinase 3 [(FLT3); FLT3-ITD] with tyrosine kinase inhibitor (TKI) in acute myeloid leukemia (AML) leads to clearance of blasts in the periphery but not in the bone marrow, suggesting a protective effect of the marrow niche on leukemic stem cells. In this study, we examined the effect of stromal niche cells on CD34 þ progenitors from patients with FLT3-ITD þ or wild-type FLT3 (FLT3-WT) AML treated with the TKIs SU5614 or sorafenib. TKIs effectively and specifically inhibited FLT3 and increased the fraction of undivided progenitors in both FLT3-ITD þ and FLT3-WT samples. Treatment with SU5614 and sorafenib also reduced the number of mature leukemic progenitors, whereas contact with stroma protected against this cell loss. In contrast, primitive long-term progenitors from both FLT3-ITD þ and FLT3-WT AML were resistant to TKIs. Additional contact with niche cells significantly expanded long-term FLT3-ITD þ but not FLT3-WT progenitors in the presence of SU5614 but not that of sorafenib. Thus, TKIs with first-generation inhibitors fail to eradicate early leukemic stem/progenitor cells in FLT3-ITD þ AML. Further, we defined a specific interaction between FLT3-ITD þ progenitors and niche cells that enables the maintenance of leukemic progenitors in the presence of TKI. Collectively, our findings suggest that molecular therapy may have unpredicted effects on leukemic progenitors, underscoring the necessity of developing strategies to selectively eliminate the malignant stem cell clone. Cancer Res; 71(13); 4696-706. Ó2011 AACR.

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“…leukemic progenitor population increased after VPA treatment, resulting in stabilization of the leukemic stem cell compartment, 47 while Mahlknecht et al showed that treatment with VPA mobilizes leukemic blast cells from the bone marrow compartment due to reduced VLA-4 expression. 48 We further investigated the effect of HDAC inhibition on progenitor differentiation using colonyforming assays and by analyzing progenitor populations during neutrophil development.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation

Bartels¹,

Geest²,

Bierings³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundThe clinical use of chromatin-modulating drugs, such as histone deacetylase inhibitors, for the treatment of bone marrow failure and hematopoietic malignancies has increased dramatically over the last few years. Nonetheless, little is currently known concerning their effects on myelopoiesis. Design and MethodsWe utilized an ex vivo differentiation system in which umbilical cord blood-derived CD34 + cells were treated with trichostatin A, sodium butyrate and valproic acid to evaluate the effect of histone deacetylase inhibitor treatment on myeloid lineage development, colony-forming potential, proliferation, and terminal neutrophil differentiation. ResultsTrichostatin A treatment modestly reduced progenitor proliferation, while sodium butyrate and valproic acid resulted in concentration-dependent effects on proliferation and apoptosis. Addition of valproic acid uniquely stimulated CD34 + proliferation. Sodium butyrate treatment inhibited terminal neutrophil differentiation both quantitatively and qualitatively. Addition of 100 μM valproic acid resulted in increased numbers of mature neutrophils with a block in differentiation at increasing concentrations. Sodium butyrate and valproic acid treatment resulted in increased acetylation of histones 3 and 4 while trichostatin A, sodium butyrate and valproic acid had differential effects on the acetylation of non-histone proteins. ConclusionsIndividual histone deacetylase inihibitors had specific effects on cell fate decisions during myeloid development. These data provide novel insights into the effects of histone deacetylase inhibitors on the regulation of normal hematopoiesis, which is of importance when considering utilizing these compounds for the treatment of myeloid malignancies and bone marrow failure syndromes.Key words: hematopoiesis, HDAC inhibitors, neutrophil. Haematologica 2010;95:1052-1060. doi:10.3324/haematol.2009 This is an open-access paper. Citation: Bartels M, Geest CR, Bierings M, Buitenhuis M, and Coffer PJ. Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation. Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation

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Effect of histone deacetylase inhibitor valproic acid on progenitor cells of acute myeloid leukemia

Cited by 45 publications

References 17 publications

Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL

Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL

Stromal Niche Cells Protect Early Leukemic FLT3-ITD+ Progenitor Cells against First-Generation FLT3 Tyrosine Kinase Inhibitors

Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation

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