How to manage acute promyelocytic leukemia

Jq, Mi; Jm, Li; Zx, Shen; Sj, Chen; Chen, Zhiao

doi:10.1038/leu.2012.57

Cited by 84 publications

(66 citation statements)

References 99 publications

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“…60 Combined treatment with superphysiological doses of ATRA and conventional chemotherapeutic drugs or arsenic trioxide has greatly improved the outcome of patients with this disease. 60 In contrast, in non-APL AML no clear value for the addition of ATRA has so far been demonstrated. 61 Nevertheless, because dosing and scheduling may require adaptation, a potential beneficial effect of ATRA in non-APL AML is still under active investigation.…”

Section: Introductionmentioning

confidence: 99%

“…56 It enhanced the proliferation and in vivo long term repopulation ability of primitive haematopoietic precursor cells, but inhibited the proliferation and advanced the differentiation of more committed progenitor cells. [57][58][59][60] The well documented differentiation promoting properties of ATRA have been put to therapeutic use in the context of acute promyelocytic leukemia (APL), a subtype of AML characterized by the presence of RARa fusion proteins with reduced sensitivity to ATRA. 60 Combined treatment with superphysiological doses of ATRA and conventional chemotherapeutic drugs or arsenic trioxide has greatly improved the outcome of patients with this disease.…”

Section: Introductionmentioning

confidence: 99%

“…[57][58][59][60] The well documented differentiation promoting properties of ATRA have been put to therapeutic use in the context of acute promyelocytic leukemia (APL), a subtype of AML characterized by the presence of RARa fusion proteins with reduced sensitivity to ATRA. 60 Combined treatment with superphysiological doses of ATRA and conventional chemotherapeutic drugs or arsenic trioxide has greatly improved the outcome of patients with this disease. 60 In contrast, in non-APL AML no clear value for the addition of ATRA has so far been demonstrated.…”

Section: Introductionmentioning

confidence: 99%

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The oncogeneEVI1enhances transcriptional and biological responses of human myeloid cells toall-transretinoic acid

Steinmetz¹,

Hackl²,

Slabáková³

et al. 2014

Cell Cycle

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The product of the ecotropic virus integration site 1 (EVI1) gene, whose overexpression is associated with a poor prognosis in myeloid leukemias and some epithelial tumors, regulates gene transcription both through direct DNA binding and through modulation of the activity of other sequence specific transcription factors. Previous results from our laboratory have shown that EVI1 influenced transcription regulation in response to the myeloid differentiation inducing agent, all-trans retinoic acid (ATRA), in a dual manner: it enhanced ATRA induced transcription of the RARb gene, but repressed the ATRA induction of the EVI1 gene itself. In the present study, we asked whether EVI1 would modulate the ATRA regulation of a larger number of genes, as well as biological responses to this agent, in human myeloid cells. U937 and HL-60 cells ectopically expressing EVI1 through retroviral transduction were subjected to microarray based gene expression analysis, and to assays measuring cellular proliferation, differentiation, and apoptosis. These experiments showed that EVI1 modulated the ATRA response of several dozens of genes, and in fact reinforced it in the vast majority of cases. A particularly strong synergy between EVI1 and ATRA was observed for GDF15, which codes for a member of the TGF-b superfamily of cytokines. In line with the gene expression results, EVI1 enhanced cell cycle arrest, differentiation, and apoptosis in response to ATRA, and knockdown of GDF15 counteracted some of these effects. The potential clinical implications of these findings are discussed.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The oncogeneEVI1enhances transcriptional and biological responses of human myeloid cells toall-transretinoic acid

Steinmetz¹,

Hackl²,

Slabáková³

et al. 2014

Cell Cycle

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“…27,28 All-trans retinoic acid (ATRA), a potent activator of cellular growth arrest, differentiation, and death of APL cells, has been shown to effectively promote complete clinical remission of APL when combined with chemotherapy. [29][30][31] Despite the success of this treatment, some APL patients are refractory to ATRA treatment or relapse owing to the development of resistance to ATRA in leukemia cells. [32][33][34] Our previous results revealed that autophagy flux is activated during granulocyte differentiation of myeloid leukemia cell lines induced by ATRA.…”

mentioning

confidence: 99%

p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells

et al. 2014

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The p62/SQSTM1 adapter protein has an important role in the regulation of several key signaling pathways and helps transport ubiquitinated proteins to the autophagosomes and proteasome for degradation. Here, we investigate the regulation and roles of p62/SQSTM1 during acute myeloid leukemia (AML) cell maturation into granulocytes. Levels of p62/SQSTM1 mRNA and protein were both significantly increased during all-trans retinoic acid (ATRA)-induced differentiation of AML cells through a mechanism that depends on NF-jB activation. We show that this response constitutes a survival mechanism that prolongs the life span of mature AML cells and mitigates the effects of accumulation of aggregated proteins that occurs during granulocytic differentiation. Interestingly, ATRA-induced p62/SQSTM1 upregulation was impaired in maturation-resistant AML cells but was reactivated when differentiation was restored in these cells. Primary blast cells of AML patients and CD34 þ progenitors exhibited significantly lower p62/SQSTM1 mRNA levels than did mature granulocytes from healthy donors. Our results demonstrate that p62/SQSTM1 expression is upregulated in mature compared with immature myeloid cells and reveal a prosurvival function of the NF-jB/SQSTM1 signaling axis during granulocytic differentiation of AML cells. These findings may help our understanding of neutrophil/granulocyte development and will guide the development of novel therapeutic strategies for refractory and relapsed AML patients with previous exposure to ATRA.

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“…We have also tested the effect of ATRA, which is part of the standard treatment in AML associated with PML-RARA. 47 We observed that treatment with ATRA did not increase the expression of CD48 both in the U937 transfected cells (supplemental Figure 3A) or in cells, which endogenously express the fusion proteins (NB4 and Kasumi-1) (supplemental Figure 3B). …”

Section: The Downregulation Of Cd48 By the Oncogenic Proteins Is Medimentioning

confidence: 83%

Immune evasion by oncogenic proteins of acute myeloid leukemia

Elias¹,

Yamin²,

Golomb

et al. 2014

Blood

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Key Points• PML-RARA and AML1-ETO evade NK cell recognition by specifically downregulating the expression of CD48.• The findings are relevant to AML patients bearing these specific translocations.PML-RARA and AML1-ETO are important oncogenic fusion proteins that play a central role in transformation to acute myeloid leukemia (AML). Whether these fusion proteins render the tumor cells with immune evasion properties is unknown. Here we show that both oncogenic proteins specifically downregulate the expression of CD48, a ligand of the natural killer (NK) cell activating receptor 2B4, thereby leading to decreased killing by NK cells. We demonstrate that this process is histone deacetylase (HDAC)-dependent, that it is mediated through the downregulation of CD48 messenger RNA, and that treatment with HDAC inhibitors (HDACi) restores the expression of CD48. Furthermore, by using chromatin immuoprecepitation (ChIP) experiments, we show that AML1-ETO directly interacts with CD48. Finally, we show that AML patients who are carrying these specific translocations have low expression of CD48. (Blood. 2014;123(10):1535-1543 Introduction Acute myeloid leukemia (AML) is the most common acute leukemia in adults. 1 There are several types of AML (approximately 30%) that are characterized by chromosomal translocations, which generate oncogenic fusion proteins.2 Two of the most common translocations in AML are t(15:17), which gives rise to the fusion protein PML-RARA, and t(8:21), which generates the fusion protein RUNX1-RUNX1T1 (AML1-ETO).3,4 Although these fusion proteins were discovered more than 20 years ago, 5,6 it is not known whether they provide immune evasion properties to AML tumors.Over the past few decades it has been established that natural killer (NK) cells, which are part of the innate immune system, play an important role in killing cancerous cells, 7,8 and specifically AML cells. 9,10 Several studies have found that AML patients who received transplants from NK alloreactive donors had lower relapse rates and improved disease-free survival. [11][12][13] Furthermore, it was recently reported that the presence of the NK cell receptor KIR2DS1, in matched unrelated donors, is associated with distinct outcomes of allogeneic hematopoietic stem cell transplantation in AML patients. 14 Finally, it was shown in several studies that NK cell activity correlates with clinical parameters of AML patients. 15,16 Killing by NK cells is mediated by several killer receptors that recognize distinct ligands. [17][18][19][20][21][22][23][24] Several human killer receptors, such as NKp44 and NKp30, have no mouse orthologs, and others, such as 2B4, have a mouse ortholog protein with opposing functions. In humans, 2B4 functions as an activating receptor, [25][26][27] whereas in mice, it mainly functions as an inhibitory receptor. 28,29 However, in both cases it recognizes CD48. [25][26][27][28] Despite the crucial role played by NK cells in eliminating AML tumors, the NK cell recognition of AML tumor cells is impaired at several levels (r...

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How to manage acute promyelocytic leukemia

Cited by 84 publications

References 99 publications

The oncogeneEVI1enhances transcriptional and biological responses of human myeloid cells toall-transretinoic acid

The oncogeneEVI1enhances transcriptional and biological responses of human myeloid cells toall-transretinoic acid

p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells

Immune evasion by oncogenic proteins of acute myeloid leukemia

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