Myeloid leukemia factor

Gobert, Vanessa; Haenlin, Marc; Waltzer, Lucas

doi:10.4161/trns.21490

Cited by 14 publications

(10 citation statements)

References 29 publications

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“…In contrast, a point mutation (P32S) in the highly conserved HPD loop crucial for Hsc70 activation [ 36 ], deletion of the J-domain or deletion of the J and G/F domains did not affect the interaction between DnaJ-1 and GFP-MLF. MLF does not harbor characteristic domains apart from a central “MLF homology domain” (MHD, amino acids 96 to 202) conserved between MLF family members [ 15 ]. Using GFP-DnaJ-1 as bait and MLF deletion mutants as preys, we found that the MHD was sufficient for binding DnaJ-1, while MLF N- and C-terminal regions were dispensable ( Fig 1D ).…”

Section: Resultsmentioning

confidence: 99%

“…MLF1 is the founding member of a small evolutionarily conserved family of nucleo-cytoplasmic proteins present in all metazoans but lacking recognizable domains that could help define their biochemical activity [ 15 ]. Whereas vertebrates have two closely related MLF paralogs, Drosophila has a single mlf gene encoding a protein that displays around 50% identity with human MLF in the central conserved domain [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover phenotypic defects associated with MLF loss in Drosophila can be rescued by human MLF1 [ 17 , 26 ]. Thus MLF function seems conserved during evolution and Drosophila appears to be a genuine model organism to characterize MLF proteins [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Control of RUNX-induced repression of Notch signaling by MLF and its partner DnaJ-1 during Drosophila hematopoiesis

et al. 2017

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A tight regulation of transcription factor activity is critical for proper development. For instance, modifications of RUNX transcription factors dosage are associated with several diseases, including hematopoietic malignancies. In Drosophila, Myeloid Leukemia Factor (MLF) has been shown to control blood cell development by stabilizing the RUNX transcription factor Lozenge (Lz). However, the mechanism of action of this conserved family of proteins involved in leukemia remains largely unknown. Here we further characterized MLF’s mode of action in Drosophila blood cells using proteomic, transcriptomic and genetic approaches. Our results show that MLF and the Hsp40 co-chaperone family member DnaJ-1 interact through conserved domains and we demonstrate that both proteins bind and stabilize Lz in cell culture, suggesting that MLF and DnaJ-1 form a chaperone complex that directly regulates Lz activity. Importantly, dnaj-1 loss causes an increase in Lz+ blood cell number and size similarly as in mlf mutant larvae. Moreover we find that dnaj-1 genetically interacts with mlf to control Lz level and Lz+ blood cell development in vivo. In addition, we show that mlf and dnaj-1 loss alters Lz+ cell differentiation and that the increase in Lz+ blood cell number and size observed in these mutants is caused by an overactivation of the Notch signaling pathway. Finally, using different conditions to manipulate Lz activity, we show that high levels of Lz are required to repress Notch transcription and signaling. All together, our data indicate that the MLF/DnaJ-1-dependent increase in Lz level allows the repression of Notch expression and signaling to prevent aberrant blood cell development. Thus our findings establish a functional link between MLF and the co-chaperone DnaJ-1 to control RUNX transcription factor activity and Notch signaling during blood cell development in vivo.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Control of RUNX-induced repression of Notch signaling by MLF and its partner DnaJ-1 during Drosophila hematopoiesis

et al. 2017

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“…p62 has also been found in other inclusion disorders, including FTD, PD, and AD [49, 88, 154]. A third protein enriched in FXTAS inclusions, MLF2, has previously been found to co-aggregate with p62 and poly (gly-ala) in mice, and it alleviated poly-Q associated toxicity in Drosophila and rat models [36, 124]. The presence of MBP enrichment in FXTAS inclusions is not well understood, as MBP is traditionally known to be a cytoplasmic oligodendrocyte protein associated with myelination.…”

Section: Discussionmentioning

confidence: 99%

Composition of the Intranuclear Inclusions of Fragile X-associated Tremor/Ataxia Syndrome

Herren

Espinal

et al. 2019

acta neuropathol commun

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Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder associated with a premutation repeat expansion (55–200 CGG repeats) in the 5′ noncoding region of the FMR1 gene. Solitary intranuclear inclusions within FXTAS neurons and astrocytes constitute a hallmark of the disorder, yet our understanding of how and why these bodies form is limited. Here, we have discovered that FXTAS inclusions emit a distinct autofluorescence spectrum, which forms the basis of a novel, unbiased method for isolating FXTAS inclusions by preparative fluorescence-activated cell sorting (FACS). Using a combination of autofluorescence-based FACS and liquid chromatography/tandem mass spectrometry (LC-MS/MS)-based proteomics, we have identified more than two hundred proteins that are enriched within the inclusions relative to FXTAS whole nuclei. Whereas no single protein species dominates inclusion composition, highly enriched levels of conjugated small ubiquitin-related modifier 2 (SUMO 2) protein and p62/sequestosome-1 (p62/SQSTM1) protein were found within the inclusions. Many additional proteins involved with RNA binding, protein turnover, and DNA damage repair were enriched within inclusions relative to total nuclear protein. The current analysis has also allowed the first direct detection, through peptide sequencing, of endogenous FMRpolyG peptide, the product of repeat-associated non-ATG (RAN) translation of the FMR1 mRNA. However, this peptide was found only at extremely low levels and not within whole FXTAS nuclear preparations, raising the question whether endogenous RAN products exist at quantities sufficient to contribute to FXTAS pathogenesis. The abundance of the inclusion-associated ubiquitin- and SUMO-based modifiers supports a model for inclusion formation as the result of increased protein loads and elevated oxidative stress leading to maladaptive autophagy. These results highlight the need to further investigate FXTAS pathogenesis in the context of endogenous systems. Electronic supplementary material The online version of this article (10.1186/s40478-019-0796-1) contains supplementary material, which is available to authorized users.

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“…Some fruit fly AML models involved the myeloid leukemia factor ( MLF ), which is a family of conserved genes coding for small proteins that act in nucleo-cytoplasmic shuttling. In patients with myelodysplastic syndrome (MDS) and AML, human MLF (hMLF1) was characterized as a target of the t(3;5) (q25.1;q34) translocation producing the fusion protein between the entire hMLF1 and the N-terminal domain of nucleophosmin (NPM1) [ 113 ]. Interestingly, Drosophila mlf was demonstrated to stabilize Lz as means to regulate lz+ cells and to maintain the lymph gland homeostasis keeping the cells in a progenitor state.…”

Section: Leukemia Models In Drosophila Melanogastermentioning

confidence: 99%

The Leukemic Fly: Promises and Challenges

Outa

Abubaker

Madi

et al. 2020

Cells

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Leukemia involves different types of blood cancers, which lead to significant mortality and morbidity. Murine models of leukemia have been instrumental in understanding the biology of the disease and identifying therapeutics. However, such models are time consuming and expensive in high throughput genetic and drug screening. Drosophila melanogaster has emerged as an invaluable in vivo model for studying different diseases, including cancer. Fruit flies possess several hematopoietic processes and compartments that are in close resemblance to their mammalian counterparts. A number of studies succeeded in characterizing the fly’s response upon the expression of human leukemogenic proteins in hematopoietic and non-hematopoietic tissues. Moreover, some of these studies showed that these models are amenable to genetic screening. However, none were reported to be tested for drug screening. In this review, we describe the Drosophila hematopoietic system, briefly focusing on leukemic diseases in which fruit flies have been used. We discuss myeloid and lymphoid leukemia fruit fly models and we further highlight their roles for future therapeutic screening. In conclusion, fruit fly leukemia models constitute an interesting area which could speed up the process of integrating new therapeutics when complemented with mammalian models.

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Myeloid leukemia factor

Cited by 14 publications

References 29 publications

Control of RUNX-induced repression of Notch signaling by MLF and its partner DnaJ-1 during Drosophila hematopoiesis

Control of RUNX-induced repression of Notch signaling by MLF and its partner DnaJ-1 during Drosophila hematopoiesis

Composition of the Intranuclear Inclusions of Fragile X-associated Tremor/Ataxia Syndrome

The Leukemic Fly: Promises and Challenges

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