Genetic barcoding systematically compares genes in del(5q) MDS and reveals a central role for <i>CSNK1A1</i> in clonal expansion

Stalmann, Ursula; Ticconi, Fabio; Snoeren, Inge; Li, Ronghui; Gleitz, Hélène; Cowley, Glenn S.; McConkey, Marie; Wong, Aaron Benson; Schmitz, Stephani; Fuchs, Stijn N.R.; Sood, Shubhankar; Leimkühler, Nils B.; Martínez-Høyer, Sergio; Banjanin, Bella; Root, David E.; Bruemmendorf, Tim H.; Pearce, Juliette; Schuppert, Andreas; Bindels, Eric; Essers, Marieke; Heckl, Dirk; Stiehl, Thomas; Costa, Ivan G.; Ebert, Benjamin L.; Schneider, Rebekka K.

doi:10.1182/bloodadvances.2021006061

Cited by 7 publications

(17 citation statements)

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“…To date, several candidate haploinsufficient genes (e.g. EGR1, APC, CTNNA1, CDC25C, CSNK1A1 ) located in or out of 5q CDR have been studied [ 6 – 9 ]. Modification of CTNNA1 expression was shown to modulate apoptosis and proliferation in cell lines [ 7 ], while CDC25C was reported as recurrently mutated in familial platelet disorders with predisposition to acute myelogenous leukemia (FPD/AML) [ 27 ] and its dosage demonstrated as influencing the sensitivity to Lenalidomide in del(5q) MDS [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…Modification of CTNNA1 expression was shown to modulate apoptosis and proliferation in cell lines [ 7 ], while CDC25C was reported as recurrently mutated in familial platelet disorders with predisposition to acute myelogenous leukemia (FPD/AML) [ 27 ] and its dosage demonstrated as influencing the sensitivity to Lenalidomide in del(5q) MDS [ 28 ]. More recently, CSNK1A1 haploinsufficiency was shown to give an advantage to hematopoietic stem cells when compared to haploinsufficient APC or EGR1 in a chronic inflammatory context [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

“…Even though several candidate haploinsufficient genes (e.g. EGR1, APC, CTNNA1, CDC25C, CSNK1A1 ) located in or out of the common deleted region (CDR) have been proposed [ 6 – 9 ], the contributing genetic events leading to this poor outcome remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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DELE1 haploinsufficiency causes resistance to mitochondrial stress-induced apoptosis in monosomy 5/del(5q) AML

Spinella,

Chagraoui,

Moison

et al. 2023

Leukemia

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Monosomy 5 and deletions of the chromosome 5q (−5/del(5q)) are recurrent events in de novo adult acute myeloid leukemia (AML), reaching up to 40% of cases in secondary AML. These chromosome anomalies are associated with TP53 mutations and with very poor prognosis. Using the large Leucegene genomic and transcriptomic dataset composed of 48 −5/del(5q) patient specimens and 367 control AML, we identified DELE1 – located in the common deleted region – as the most consistently downregulated gene in these leukemias. DELE1 encodes a mitochondrial protein recently characterized as the relay of mitochondrial stress to the cytosol through a newly defined OMA1-DELE1-HRI pathway which ultimately leads to the activation of ATF4, the master transcription factor of the integrated stress response. Here, we showed that the partial loss of DELE1 expression observed in −5/del(5q) patients was sufficient to significantly reduce the sensitivity to mitochondrial stress in AML cells. Overall, our results suggest that DELE1 haploinsufficiency could represent a new driver mechanism in −5/del(5q) AML.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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DELE1 haploinsufficiency causes resistance to mitochondrial stress-induced apoptosis in monosomy 5/del(5q) AML

Spinella,

Chagraoui,

Moison

et al. 2023

Leukemia

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“…Our previous work demonstrated that Csnk1a1 haploinsufficiency leads to a proliferative advantage of HSCs by activation of Wnt signaling and Myc upregulation with concurrent downregulation of inflammatory signaling in HSCs. 10 , 17 …”

Section: Introductionmentioning

confidence: 99%

Collaborative effect of Csnk1a1 haploinsufficiency and mutant p53 in Myc induction can promote leukemic transformation

Fuchs,

Stalmann,

Snoeren

et al. 2024

Blood Advances

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It is still not fully understood how genetic haploinsufficiency in del(5q) MDS contributes to malignant transformation of hematopoietic stem cells. We asked how compound haploinsufficiency for Csnk1a1 and Egr1 in the common deleted region on chromosome 5 affects hematopoietic stem cells. Additionally, Trp53 was disrupted as the most frequently co-mutated gene in del(5q) MDS using CRISPR/Cas9 editing in hematopoietic progenitors of WT, Csnk1a1-/+, Egr1-/+, Csnk1a1/Egr1-/+ mice. A transplantable acute leukemia only developed in the Csnk1a1-/+ Trp53 edited recipient. Isolated blasts were indefinitely cultured ex vivo and gave rise to leukemia after transplantation, providing a tool to study disease mechanisms or to perform drug screenings. In a small-scale drug screening, the collaborative effect of Csnk1a1 haploinsufficiency and Trp53 sensitized blasts to the CSNK1 inhibitor A51 relative to WT or Csnk1a1 haploinsufficient cells. In vivo, A51 treatment significantly reduced blast counts in Csnk1a1 haploinsufficient/Trp53 acute leukemias and restored hematopoiesis in the bone marrow. Transcriptomics on blasts and their normal counterparts showed that the derived leukemia was driven by MAPK and Myc upregulation downstream of Csnk1a1 haploinsufficiency cooperating with a downregulated p53 axis. A collaborative effect of Csnk1a1 haploinsufficiency and p53 loss on MAPK and Myc upregulation was confirmed on the protein level. Downregulation of Myc protein expression correlated with efficient elimination of blasts in A51 treatment. The "myc signature" closely resembled the transcriptional profile of del(5q) MDS patients with TP53 mutation.

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“…Deletions of CSNK1A1, EGR1, and APC are implicated in the proliferation of hematopoietic cells. Among these genes, genetic barcoding revealed that CSNK1A1 haploinsufficiency is the major driver of clonal expansion of del(5q) MDS HSPCs 15 . CSNK1A1 and APC are both regulators of b-catenin function, which is thought to contribute to stem cell-self renewal programs in del(5q) HSCPs.…”

Section: Introductionmentioning

confidence: 99%

Chronic inflammation suppresses del(5q)-like MDS HSCs via p53

Muto

Walker

Choi

et al. 2022

Preprint

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Inflammation is associated with the pathogenesis of Myelodysplastic syndromes (MDS). Emerging evidence suggests that MDS hematopoietic stem and progenitor cells (HSPCs) exhibit an altered response to systemic low-grade inflammation, which contributes to their competitive advantage over wild-type HSPCs and ensuing hematopoietic defects. Deletion of the long arm of chromosome 5 (del(5q)) is the most common chromosomal abnormality in patients with MDS. Although this subtype of MDS contains several haploinsufficient genes that directly impact innate immune signaling, the effects of an inflammatory milieu on del(5q) MDS HSPCs remains poorly defined. Utilizing a model of del(5q)-like MDS, wherein two 5q genes, miR-146a and TIFAB, are deleted, we found that chronic low-grade inflammation impaired the function of del(5q)-like MDS HSPCs and contributed to a more severe disease. The del(5q)-like MDS HSPCs exposed to chronic inflammation became less quiescent, but without changes in cell viability. In response to inflammation, mouse and human del(5q) MDS HSPCs activated a partial p53 response. The impaired function and reduced cellular quiescence of del(5q) MDS HSPCs exposed to inflammation could be restored by deletion of p53. Since TP53 mutations are highly enriched in del(5q) AML patients following an initial MDS diagnosis, increased p53 activation in del(5q) MDS HSPCs due to inflammation may create a selective pressure for genetic inactivation of p53. These findings uncover the contribution of systemic inflammation on dyshematopoiesis in del(5q) MDS and provide a potential explanation for acquired p53 mutations in myeloid malignancies with del(5q).

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Genetic barcoding systematically compares genes in del(5q) MDS and reveals a central role for CSNK1A1 in clonal expansion

Cited by 7 publications

References 50 publications

DELE1 haploinsufficiency causes resistance to mitochondrial stress-induced apoptosis in monosomy 5/del(5q) AML

DELE1 haploinsufficiency causes resistance to mitochondrial stress-induced apoptosis in monosomy 5/del(5q) AML

Collaborative effect of Csnk1a1 haploinsufficiency and mutant p53 in Myc induction can promote leukemic transformation

Chronic inflammation suppresses del(5q)-like MDS HSCs via p53

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