Biological features of primary APL blasts: their relevance to the understanding of granulopoiesis, leukemogenesis and patient management

Cassinat, Bruno; Chomienne, Christine

doi:10.1038/sj.onc.1204761

Cited by 16 publications

(12 citation statements)

References 87 publications

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“…These cells also expressed the myeloid precursor marker CD33 (20,21) and MHC class I, but not hematopoietic stem cell/progenitor cell marker CD34 (58) or MHC class II. This unique phenotype of CD33 + CD34 -MHC class I + class II -is consistent with that of promyelocytes (59)(60)(61)(62). We also observed strong G-CSFR staining on MDL-1 + cells, which is in accordance with two previous studies reporting that G-CSFR is highly expressed on CD33 + CD34 -human bone marrow cells (63,64) and provides further evidence that the MDL-1-expressing pathogenic cells are immature myeloid cells/promyelocytes.…”

Section: Figuresupporting

confidence: 80%

Activation of MDL-1 (CLEC5A) on immature myeloid cells triggers lethal shock in mice

Cheung¹,

Shen²,

Phillips³

et al. 2011

J. Clin. Invest.

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Systemic inflammatory response syndrome (SIRS) is a potentially lethal condition, as it can progress to shock, multi-organ failure, and death. It can be triggered by infection, tissue damage, or hemorrhage. The role of tissue injury in the progression from SIRS to shock is incompletely understood. Here, we show that treatment of mice with concanavalin A (ConA) to induce liver injury triggered a G-CSF-dependent hepatic infiltration of CD11b + Gr-1 + Ly6G + Ly6C + immature myeloid cells that expressed the orphan receptor myeloid DAP12-associated lectin-1 (MDL-1; also known as CLEC5A). Activation of MDL-1 using dengue virus or an agonist MDL-1-specific antibody in the ConA-treated mice resulted in shock. The MDL-1 + cells were pathogenic, and in vivo depletion of MDL-1 + cells provided protection. Triggering MDL-1 on these cells induced production of NO and TNF-α, which were found to be elevated in the serum of treated mice and required for MDL-1-induced shock. Surprisingly, MDL-1-induced NO and TNF-α production required eNOS but not iNOS. Activation of DAP12, DAP10, Syk, PI3K, and Akt was critical for MDL-1-induced shock. In addition, Akt physically interacted with and activated eNOS. Therefore, triggering of MDL-1 on immature myeloid cells and production of NO and TNF-α may play a critical role in the pathogenesis of shock. Targeting the MDL-1/Syk/PI3K/Akt/eNOS pathway represents a potential new therapeutic strategy to prevent the progression of SIRS to shock.

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Section: Figuresupporting

confidence: 80%

Activation of MDL-1 (CLEC5A) on immature myeloid cells triggers lethal shock in mice

Cheung¹,

Shen²,

Phillips³

et al. 2011

J. Clin. Invest.

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“…In the absence of ligand, the fusion protein impedes in a dominant-negative manner the expression of RAR␣ target genes and thus blocks the APL cells at the promyelocytic stage (33,36) through its ability to occupy RAREs and to interact with complexes encompassing a wide range of epigenetic enzymes with strong repressive activity toward target genes. At pharmacological concentrations, alltrans RA is a highly effective agent that induces terminal differentiation of APL cells both in vitro and in vivo (8). The differentiation process is accompanied by the release of corepressors and the subsequent activation of RAR␣ target genes (33).…”

mentioning

confidence: 99%

New Role for Granulocyte Colony-Stimulating Factor-Induced Extracellular Signal-Regulated Kinase 1/2 in Histone Modification and Retinoic Acid Receptor α Recruitment to Gene Promoters: Relevance to Acute Promyelocytic Leukemia Cell Differentiation

Cassinat

Zassadowski

Ferry

et al. 2011

Molecular and Cellular Biology

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The induction of the granulocytic differentiation of leukemic cells by all-trans retinoic acid (RA) has been a major breakthrough in terms of survival for acute promyelocytic leukemia (APL) patients. Here we highlight the synergism and the underlying novel mechanism between RA and the granulocyte colony-stimulating factor (G-CSF) to restore differentiation of RA-refractory APL blasts. First, we show that in RA-refractory APL cells (UF-1 cell line), PML-RA receptor alpha (RAR␣) is not released from target promoters in response to RA, resulting in the maintenance of chromatin repression. Consequently, RAR␣ cannot be recruited, and the RA target genes are not activated. We then deciphered how the combination of G-CSF and RA successfully restored the activation of RA target genes to levels achieved in RA-sensitive APL cells. We demonstrate that G-CSF restores RAR␣ recruitment to target gene promoters through the activation of the extracellular signalregulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and the subsequent derepression of chromatin. Thus, combinatorial activation of cytokines and RARs potentiates transcriptional activity through epigenetic modifications induced by specific signaling pathways.

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“…Autophagy also participates in the differentiation of both B- and T-lymphocytes [35], plasma cells [16] and monocytes [36]. Despite the confounding presence of an abnormal fusion oncoprotein, the ATRA-mediated differentiation of APL cells in culture has long been used as a model for normal myelopoiesis [37]. Our study performed on a leukemic cell line model may have broader application, also suggesting a role for autophagy in normal myelopoiesis.…”

Section: Discussionmentioning

confidence: 93%

Induction of autophagy is a key component of all-trans-retinoic acid-induced differentiation in leukemia cells and a potential target for pharmacologic modulation

Orfali

O’Donovan

Nyhan

et al. 2015

Experimental Hematology

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Acute myeloid leukemia (AML) is characterized by the accumulation of immature blood cell precursors in the bone marrow. Pharmacologically overcoming the differentiation block in this condition is an attractive therapeutic avenue, which has only achieved success in a subtype of AML, acute promyelocytic leukemia (APL). Attempts to emulate this success in other AML subtypes have thus far been unsuccessful. Autophagy is a conserved protein degradation pathway with important roles in mammalian cell differentiation, particularly within the hematopoietic system. In this study we demonstrate the functional importance of autophagy in APL cell differentiation. We show that autophagy is increased during ATRA-induced granulocytic differentiation of the APL cell line NB4, and that this is associated with increased expression of LC3-II and GATE-16 proteins involved in autophagosome formation. Autophagy inhibition, using either drugs (chloroquine/3-methyladenine) or short-hairpin (sh)RNA targeting the essential autophagy gene ATG7, attenuates myeloid differentiation. Importantly, we show that enhancing autophagy promotes ATRA-induced granulocytic differentiation of an ATRA-resistant derivative of the non-APL AML HL60 cell line (HL60-Diff-R). These data support the development of strategies to stimulate autophagy as a novel approach to promote differentiation in AML.

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Biological features of primary APL blasts: their relevance to the understanding of granulopoiesis, leukemogenesis and patient management

Cited by 16 publications

References 87 publications

Activation of MDL-1 (CLEC5A) on immature myeloid cells triggers lethal shock in mice

Activation of MDL-1 (CLEC5A) on immature myeloid cells triggers lethal shock in mice

New Role for Granulocyte Colony-Stimulating Factor-Induced Extracellular Signal-Regulated Kinase 1/2 in Histone Modification and Retinoic Acid Receptor α Recruitment to Gene Promoters: Relevance to Acute Promyelocytic Leukemia Cell Differentiation

Induction of autophagy is a key component of all-trans-retinoic acid-induced differentiation in leukemia cells and a potential target for pharmacologic modulation

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