BAD-LAMP is a novel biomarker of nonactivated human plasmacytoid dendritic cells

Defays, Axel; David, Alexandre; Gassart, Aude De; Rigotti, Francesca; Wenger, Till; Camossetto, Voahirana; Brousset, Pierre; Petrella, Tony; Dalod, Marc; Gatti, Evelina; Pierre, Philippe

doi:10.1182/blood-2010-11-319699

Cited by 29 publications

(41 citation statements)

References 40 publications

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“…In contrast to the intrinsic resistance of MLL chimeras to UPS degradation, the sustained activation of LAMP5 in MLL leukemia suppresses the cellular autophagy process to maintain the level of MLL fusion proteins. Notably, LAMP5 expression is restricted only to a few tissue types, including nonactivated pDCs in normal hematopoiesis (15,43) and MLL fusion leukemia. This exclusive expression pattern in MLL leukemia suggests that LAMP5 is a valuable target in these diseases, and targeting LAMP5 may be effective without major unwanted effects.…”

Section: Discussionmentioning

confidence: 99%

“…It is also noteworthy that LAMP5 has been suggested to function as a co-chaperone with UNC93B1, a known toll-like receptor (TLR) chaperone, to shuttle TLRs to their respective locations in the endosomes (43) and indirectly responses to immunomodulation (15). Thus, further investigation into whether LAMP5 plays any other autophagy-independent roles in MLL leukemia will assist in fully understanding its specific function for the disease.…”

Section: Discussionmentioning

confidence: 99%

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Activation of the Lysosome-Associated Membrane Protein LAMP5 by DOT1L Serves as a Bodyguard for MLL Fusion Oncoproteins to Evade Degradation in Leukemia

Wang

Han

Sun

et al. 2019

Clinical Cancer Research

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Purpose: Despite many attempts to understand mixedlineage leukemia (MLL leukemia), effective therapies for this disease remain limited. We identified a lysosome-associated membrane protein (LAMP) family member, LAMP5, that is specifically and highly expressed in patients with MLL leukemia. The purpose of the study was to demonstrate the functional relevance and clinical value of LAMP5 in the disease. Experimental Design: We first recruited a large cohort of leukemia patients to validate LAMP5 expression and evaluate its clinical value. We then performed in vitro and in vivo experiments to investigate the functional relevance of LAMP5 in MLL leukemia progression or maintenance. Results: LAMP5 was validated as being specifically and highly expressed in patients with MLL leukemia and was associated with a poor outcome. Functional studies showed that LAMP5 is a novel autophagic suppressor and protects MLL fusion proteins from autophagic degradation. Specifically targeting LAMP5 significantly promoted degradation of MLL fusion proteins and inhibited MLL leukemia progression in both an animal model and primary cells. We further revealed that LAMP5 is a direct target of the H3K79 histone methyltransferase DOT1L. Downregulating LAMP5 with a DOT1L inhibitor enhanced the selective autophagic degradation of MLL oncoproteins and extended survival in vivo; this observation was especially significant when combining DOT1L inhibitors with LAMP5 knockdown. Conclusions: This study demonstrates that LAMP5 serves as a "bodyguard" for MLL fusions to evade degradation and is the first to link H3K79 methylation to autophagy regulation, highlighting the potential of LAMP5 as a therapeutic target for MLL leukemia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Activation of the Lysosome-Associated Membrane Protein LAMP5 by DOT1L Serves as a Bodyguard for MLL Fusion Oncoproteins to Evade Degradation in Leukemia

Wang

Han

Sun

et al. 2019

Clinical Cancer Research

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“…Blastic plasmacytoid dendritic cell neoplasm consists of clonal proliferation of plasmacytoid dendritic cells precursors. Previously known under different names owing to the uncertainty of its histogenesis (eg, agranular CD4 + natural killer (NK) cell leukemia, 52 blastic NK-cell leukemia/lymphoma, 53 agranular CD4 + , CD56 + hematodermic neoplasm 34 or tumor, 54 and blastic NK-cell lymphoma 55 ), a relationship to plasmacytoid dendritic cells was first hypothesized by Lucio et al, 56 and subsequently supported by phenotypic, 34,39,41,[57][58][59][60][61][62][63][64][65] molecular, 57,66 and functional data, 58,67 including the ability of tumor cells to produce IFN-I 57,58,64 and to differentiate into dendritic cells. 57,58,68 In blastic plasmacytoid dendritic cell neoplasm patients, cell lines generated from the circulating neoplastic component recapitulate to a large extent the biological properties of plasmacytoid dendritic cells.…”

Section: Blastic Plasmacytoid Dendritic Cell Neoplasmmentioning

confidence: 99%

Neoplasms derived from plasmacytoid dendritic cells

et al. 2016

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Plasmacytoid dendritic cell neoplasms manifest in two clinically and pathologically distinct forms. The first variant is represented by nodular aggregates of clonally expanded plasmacytoid dendritic cells found in lymph nodes, skin, and bone marrow ('Mature plasmacytoid dendritic cells proliferation associated with myeloid neoplasms'). This entity is rare, although likely underestimated in incidence, and affects predominantly males. Almost invariably, it is associated with a myeloid neoplasm such as chronic myelomonocytic leukemia or other myeloid proliferations with monocytic differentiation. The concurrent myeloid neoplasm dominates the clinical pictures and guides treatment. The prognosis is usually dismal, but reflects the evolution of the associated myeloid leukemia rather than progressive expansion of plasmacytoid dendritic cells. A second form of plasmacytoid dendritic cells tumor has been recently reported and described as 'blastic plasmacytoid dendritic cell neoplasm'. In this tumor, which is characterized by a distinctive cutaneous and bone marrow tropism, proliferating cells derive from immediate CD4(+)CD56(+) precursors of plasmacytoid dendritic cells. The diagnosis of this form can be easily accomplished by immunohistochemistry, using a panel of plasmacytoid dendritic cells markers. The clinical course of blastic plasmacytoid dendritic cell neoplasm is characterized by a rapid progression to systemic disease via hematogenous dissemination. The genomic landscape of this entity is currently under intense investigation. Recurrent somatic mutations have been uncovered in different genes, a finding that may open important perspectives for precision medicine also for this rare, but highly aggressive leukemia.

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“…Notably, the largest group of lncRNA-associated mRNAs encodes membrane proteins. For example, ENST00000443469, the most highly expressed lncRNA in our profile, was found to be correlated with its adjacent gene, LAMP5, a lysosomal-associated membrane protein that is upregulated in non-activated human plasmacytoid dendritic cells and may be involved in endocytosis (23,35). And a study about the gene expression profiling of MLL-r infant ALL (36) showed that the LAMP5 (also called C20orf103) is one of the most upregulated genes in the MLL-r ALL compared with other infant ALL and pediatric precursor B-ALL, implying the impressive roles of LAMP5 and ENST00000443469 in the MLL-r ALL.…”

mentioning

confidence: 91%

A distinct set of long non-coding RNAs in childhood MLL-rearranged acute lymphoblastic leukemia: biology and epigenetic target

Fang

Han

Chen

et al. 2014

Human Molecular Genetics

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Long non-coding RNAs (lncRNAs) have been recently found to be pervasively transcribed in human genome and link to diverse human diseases. However, the expression patterns and regulatory roles of lncRNAs in hematopoietic malignancies have not been reported. Here, we carried out a genome-wide lncRNA expression study in MLL-rearranged acute lymphoblastic leukemia (MLL-r ALL) and established lncRNA/messenger RNA coexpression networks to gain insight into the biological roles of these dysregulated lncRNAs. We detected a number of lncRNAs that were differentially expressed in MLL-r ALL samples compared with MLL-r wild-type and identified unique lncRNA expression patterns between MLL-r subtypes with different translocations as well as between infant MLL-r ALL with other MLL-r ALL patients, suggesting that they might be served as novel biomarkers for the disease. Importantly, several lncRNAs that correspond with membrane protein genes, including a lysosome-associated membrane protein, were identified. No such link between the membrane proteins and MLL-r leukemia has been reported previously. Impressively, the functional analysis showed that several lncRNAs corresponded to the expression of MLL-fusion protein target genes, including HOXA9, MEIS1, etc., while some other associated with histone-related functions or membrane proteins. Further experiments characterize the effect of some lncRNAs on MLL-r leukemia apoptosis and proliferation as the function of the coexpressed HOXA gene cluster. Finally, a set of lncRNAs epigenetically regulated by H3K79 methylation were also discovered. These findings may provide novel insights into the mechanisms of lncRNAs involved in the initiation of MLL-r leukemia. This is the first study linking lncRNAs to leukemogenesis.

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BAD-LAMP is a novel biomarker of nonactivated human plasmacytoid dendritic cells

Cited by 29 publications

References 40 publications

Activation of the Lysosome-Associated Membrane Protein LAMP5 by DOT1L Serves as a Bodyguard for MLL Fusion Oncoproteins to Evade Degradation in Leukemia

Activation of the Lysosome-Associated Membrane Protein LAMP5 by DOT1L Serves as a Bodyguard for MLL Fusion Oncoproteins to Evade Degradation in Leukemia

Neoplasms derived from plasmacytoid dendritic cells

A distinct set of long non-coding RNAs in childhood MLL-rearranged acute lymphoblastic leukemia: biology and epigenetic target

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