TFEB-mediated endolysosomal activity controls human hematopoietic stem cell fate

García‐Prat, Laura; Kaufmann, Kerstin B.; Schneiter, Florin; Voisin, Véronique; Murison, Alex; Chen, Jocelyn; Chan-Seng-Yue, Michelle; Gan, Olga I.; McLeod, Jessica; Smith, Sabrina; Shoong, Michelle; Parris, Darrien; Pan, Kristele; Zeng, Andy G.X.; Krivdova, Gabriela; Gupta, Kinam; Takayanagi, Shin‐ichiro; Wagenblast, Elvin; Wang, Weijia; Lupien, Mathieu; Schroeder, Timm; Xie, Stephanie Z.; Dick, John E.

doi:10.1016/j.stem.2021.07.003

Cited by 93 publications

(109 citation statements)

References 53 publications

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“…Furthermore, lysosomes are asymmetrically distributed during division of stem cells, and thus predictive of future daughter cell fates 67 . Lysosomes also impact the fate of long-term HSCs through their ability to sense diverse cellular cues and coordinate signal transduction of pathways including cell cycling and metabolism 68 . In leukemia, increased lysosomal mass and biogenesis in leukemic progenitor cells selectively sensitizes AML cells to lysosomal inhibitors or disruptors 69, 70 .…”

Section: Discussionmentioning

confidence: 99%

INPP4B drives lysosome biogenesis to restrict leukemic stem cell differentiation and promote leukemogenesis

Woolley

Chen

Genc

et al. 2021

Preprint

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Despite an increased understanding of leukemogenesis, specific mechanisms that underlie stemness in leukemia remain largely undefined. Here, we report a novel pathway which regulates leukemic differentiation through control of lysosomal biology. We show that disruption of INPP4B results in dysregulated lysosomal gene networks, reduced lysosomal numbers and proteolytic capacity in leukemia. Inpp4b-deficient HSCs and LSCs are functionally compromised. Inpp4b-deficient leukemia models develop more differentiated leukemias with reduced disease initiating potential, and improved overall survival compared to Inpp4b-expressing leukemias. Together, our data is consistent with a model where INPP4B restricts differentiation of LSCs through regulation of lysosomal function. These data provide a mechanism to explain the association of INPP4B with aggressive AML and highlight avenues for LSC-specific leukemia therapies.

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Section: Discussionmentioning

confidence: 99%

INPP4B drives lysosome biogenesis to restrict leukemic stem cell differentiation and promote leukemogenesis

Woolley

Chen

Genc

et al. 2021

Preprint

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“…In addition, CDK4 also phosphorylates FLCN, facilitating mTORC1 recruitment to lysosomes and its activation [162]. MYC, which acts upstream of CDK4, suppresses catabolic endolysosomal pathways in proliferating cells by directly binding to the promoters of lysosomal and autophagy genes, competing with TFEB [165,166]. Nevertheless, CDK4 appears to be required to keep lysosomal function intact in cancer cells [162].…”

Section: Regulation Of Lysosomes By the Cell Cycle Machinerymentioning

confidence: 99%

“…Quiescent hematopoietic stem cells (HSCs) are enriched in lysosomes and express high levels of lysosomal genes but exhibit low lysosomal activity, and these features are required to maintain quiescence and potency (Figure 8) [156,166]. Mechanistically, TFEB-mediated activation of lysosomal genes leads to degradation of TFR1 (membrane transferrin receptor 1), which uptakes ironbound transferrin, causing unresponsiveness of cells to mitogenic signals and sustaining a hypo-metabolic quiescent state [166]. Exit from dormancy is achieved when MYC counteracts TFEB activity, allowing cells to shut down their catabolism and induce anabolism by upregulating mitochondrial and pro-proliferative genes [166].…”

Section: Role Of the Lysosomal Machinery In Adult Stem Cellsmentioning

confidence: 99%

“…Mechanistically, TFEB-mediated activation of lysosomal genes leads to degradation of TFR1 (membrane transferrin receptor 1), which uptakes ironbound transferrin, causing unresponsiveness of cells to mitogenic signals and sustaining a hypo-metabolic quiescent state [166]. Exit from dormancy is achieved when MYC counteracts TFEB activity, allowing cells to shut down their catabolism and induce anabolism by upregulating mitochondrial and pro-proliferative genes [166]. Importantly, TFEB was shown to drive the expression of myeloid-associated genes and to inhibit the expression of transcription factors associated with erythrocyte and megakaryocyte differentiation, such as GATA1 or RUNX1.…”

Section: Role Of the Lysosomal Machinery In Adult Stem Cellsmentioning

confidence: 99%

“…Thus, TFEB overexpression results in a myeloid bias, whereas its silencing pushes cells towards erythroid differentiation. In fine, the balance between TFEB and MYC activity is a crucial determinant of human HSC metabolism and fate [166]. Interestingly, lysosomes are asymmetrically inherited by HSC progeny [201].…”

Section: Role Of the Lysosomal Machinery In Adult Stem Cellsmentioning

confidence: 99%

See 2 more Smart Citations

Lysosomes at the Crossroads of Cell Metabolism, Cell Cycle, and Stemness

Nowosad

Besson

2022

IJMS

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Initially described as lytic bodies due to their degradative and recycling functions, lysosomes play a critical role in metabolic adaptation to nutrient availability. More recently, the contribution of lysosomal proteins to cell signaling has been established, and lysosomes have emerged as signaling hubs that regulate diverse cellular processes, including cell proliferation and cell fate. Deciphering these signaling pathways has revealed an extensive crosstalk between the lysosomal and cell cycle machineries that is only beginning to be understood. Recent studies also indicate that a number of lysosomal proteins are involved in the regulation of embryonic and adult stem cell fate and identity. In this review, we will focus on the role of the lysosome as a signaling platform with an emphasis on its function in integrating nutrient sensing with proliferation and cell cycle progression, as well as in stemness-related features, such as self-renewal and quiescence.

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Both intrinsic and microenvironmental factors contribute to the regulation of stem cell quiescence

Zhou,

Hu,

et al. 2024

Journal Cellular Physiology

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Precise regulation of stem cell quiescence is essential for tissue development and homeostasis. Therefore, its aberrant regulation is intimately correlated with various human diseases. However, the detailed mechanisms of stem cell quiescence and its specific role in the pathogenesis of various diseases remain to be determined. Recent studies have revealed that the intrinsic and microenvironmental factors are the potential candidates responsible for the orderly switch between the dormant and activated states of stem cells. In addition, defects in signaling pathways related to internal and external factors of stem cells might contribute to the initiation and development of diseases by altering the dormancy of stem cells. In this review, we focus on the mechanisms underlying stem cell quiescence, especially the involvement of intrinsic and microenvironmental factors. In addition, we discuss the relationship between the anomalies of stem cell quiescence and related diseases, hopefully providing therapeutic insights for developing novel treatments.

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TFEB-mediated endolysosomal activity controls human hematopoietic stem cell fate

Cited by 93 publications

References 53 publications

INPP4B drives lysosome biogenesis to restrict leukemic stem cell differentiation and promote leukemogenesis

INPP4B drives lysosome biogenesis to restrict leukemic stem cell differentiation and promote leukemogenesis

Lysosomes at the Crossroads of Cell Metabolism, Cell Cycle, and Stemness

Both intrinsic and microenvironmental factors contribute to the regulation of stem cell quiescence

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