Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Laurent, Anouchka P.; Siret, Aurélie; Ignacimouttou, Cathy; Panchal, Kunjal; Diop, M’Boyba; Jenni, Silvia; Tsai, Yi Chien; Roos‐Weil, Damien; Aid, Zakia; Prade, Naïs; Lagarde, Stéphanie; Plassard, Damien; Daudigeos, Estelle; Droin, Nathalie; Bornhäuser, Beat; Cheung, Laurence C.; Crispino, John D.; Gaudry, Muriel; Bernard, Olivier A.; Macintyre, Elizabeth; Bonnigal, Carole Barin; Kotecha, Rishi S.; Geoerger, Birgit; Ballerini, Paola; Bourquin, Jean‐Pierre; Delabesse, Éric; Mercher, Thomas; Malinge, Sébastien

doi:10.1158/1078-0432.ccr-19-3519

Cited by 19 publications

(23 citation statements)

References 56 publications

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“…The only two samples featuring high wtRAS activity in absence of high JAK2 phosphorylation levels might activate RAS via a different pathway yet to be uncovered for DS-ALL. A very recent novel patientderived xenograft models for DS-ALL found CBL-mutant (wtRAS) cells to have as high ERK1/2-phosphorylation as KRAS-mutant cells [37]. Interestingly in the same study, the leukemia burden in both wtRAS(JAK2-mutant) and mutant-RAS xenograft models was reduced via MEKinhibitor, representing a strongly corroborating evidence to some of the conclusions of our study.…”

Section: Discussionsupporting

confidence: 89%

“…Functional consequences of an increased dose of some chromosome 21 genes may play important roles [48], and this is discussed in greater detail in "Supplementary Discussion". It will be important to unravel the mechanisms behind the actions of these chromosome 21 genes, as their specific inhibition may be an additional component to consider in combinatorial therapy approaches [37,49]. This is highlighted by very frequent observations of extra copies of chromosome 21 as acquired changes in DS and non-DS ALL, both at diagnosis, and at relapse [20,50].…”

Section: Discussionmentioning

confidence: 99%

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RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia

Koschut

Ray

et al. 2020

Oncogene

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Leukemias are routinely sub-typed for risk/outcome prediction and therapy choice using acquired mutations and chromosomal rearrangements. Down syndrome acute lymphoblastic leukemia (DS‐ALL) is characterized by high frequency of CRLF2‐rearrangements, JAK2‐mutations, or RAS‐pathway mutations. Intriguingly, JAK2 and RAS-mutations are mutually exclusive in leukemic sub‐clones, causing dichotomy in therapeutic target choices. We prove in a cell model that elevated CRLF2 in combination with constitutionally active JAK2 is sufficient to activate wtRAS. On primary clinical DS‐ALL samples, we show that wtRAS-activation is an obligatory consequence of mutated/hyperphosphorylated JAK2. We further prove that CRLF2-ligand TSLP boosts the direct binding of active PTPN11 to wtRAS, providing the molecular mechanism for the wtRAS activation. Pre‐inhibition of RAS or PTPN11, but not of PI3K or JAK‐signaling, prevented TSLP‐induced RAS‐GTP boost. Cytotoxicity assays on primary clinical DS‐ALL samples demonstrated that, regardless of mutation status, high-risk leukemic cells could only be killed using RAS‐inhibitor or PTPN11-inhibitor, but not PI3K/JAK‐inhibitors, suggesting a unified treatment target for up to 80% of DS‐ALL. Importantly, protein activities-based principal-component-analysis multivariate clusters analyzed for independent outcome prediction using Cox proportional-hazards model showed that protein‐activity (but not mutation-status) was independently predictive of outcome, demanding a paradigm-shift in patient‐stratification strategy for precision therapy in high-risk ALL.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia

Koschut

Ray

et al. 2020

Oncogene

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“…While a copy number gain of DYRK1A is expectedly seen in ALL and acute myeloid leukemia (AML) cells with abnormalities such as hyperdiploidy (e.g., MHH-CALL-2), hypertetraploidy (e.g., TALL-1), and DS (e.g., CMK), cells without gain of HSA21 also have increased DYRK1A expression, indicating that this dysregulation may occur at the transcriptional level (Figure 1B). Moreover, we found that DYRK1A protein levels were increased in both B-ALL cell lines and in patient cells (22) compared with normal human bone marrow mononuclear cells (BMMCs) (Figure 1C). A query of the pediatric cancer data set in St. Jude GenomePaint (23) demonstrated that increased DYRK1A expression is associated with worse EFS in several subtypes of B-ALL, such as hyperdiploid (HeH) and Ph-like ALL (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/JCI135937DS1), underscoring its potential role as a prognostic and therapeutic target.…”

Section: Resultsmentioning

confidence: 96%

“…We performed an in vitro kinase assay, which validated that DYRK1A phosphor-malignant B cells. The effect of DYRK1A inhibition was most striking in MHH-CALL-4 and MUTZ-5 cells, as well as in PDX cells harboring gain of HSA21 (DS-ALL-02 and HeH-ALL-09) (22), in which the IC 50 values were in the high nanomolar range. Moreover, compared with previously published DYRK1 inhibitors, including harmine (32) and INDY (33), EHT 1610 displayed more potent activity in B-ALL, T cell ALL (T-ALL), and, particularly, DS-ALL samples (Figure 2H and Supplemental Table 2).…”

Section: Resultsmentioning

confidence: 99%

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DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3

Bhansali¹,

Rammohan²,

Lee³

et al. 2021

Journal of Clinical Investigation

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DYRK1A is a serine/threonine kinase encoded on human chromosome 21 (HSA21) that has been implicated in several pathologies of Down syndrome (DS), including cognitive deficits and Alzheimer's disease. Although children with DS are predisposed to developing leukemia, especially B cell acute lymphoblastic leukemia (B-ALL), the HSA21 genes that contribute to malignancies remain largely undefined. Here, we report that DYRK1A is overexpressed and required for B-ALL. Genetic and pharmacologic inhibition of DYRK1A decreased leukemic cell expansion and suppressed B-ALL development in vitro and in vivo. Furthermore, we found that FOXO1 and STAT3, transcription factors that are indispensable for B cell development, are critical substrates of DYRK1A. Loss of DYRK1A-mediated FOXO1 and STAT3 signaling disrupted DNA damage and ROS regulation, respectively, leading to preferential cell death in leukemic B cells. Thus, we reveal a DYRK1A/FOXO1/STAT3 axis that facilitates the development and maintenance of B-ALL.

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The impact of an additional copy of chromosome 21 in B‐cell precursor acute lymphoblastic leukemia

Hormann,

Mooij,

van de Mheen

et al. 2023

Genes Chromosomes & Cancer

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A common finding in pediatric B‐cell precursor acute lymphoblastic leukemia (BCPALL) is that chromosome 21 is never lost and an extra chromosome 21 is often gained. This implies an important role for chromosome 21 in the pathobiology of BCPALL, emphasized by the increased risk of BCPALL in children with Down syndrome. However, model systems of chromosome 21 gain are lacking. We therefore developed a BCPALL cell line (Nalm‐6, DUX4‐rearranged) with an additional chromosome 21 by means of microcell‐mediated chromosome transfer. FISH, PCR, multiplex ligation‐dependent probe amplification, and whole exome sequencing showed that an additional chromosome 21 was successfully transferred to the recipient cells. Transcription of some but not all genes on chromosome 21 was increased, indicating tight transcriptional regulation. Nalm‐6 cells with an additional chromosome 21 proliferated slightly slower compared with parental Nalm‐6 and sensitivity to induction chemotherapeutics was mildly increased. The extra copy of chromosome 21 did not confer sensitivity to targeted signaling inhibitors. In conclusion, a BCPALL cell line with an additional human chromosome 21 was developed, validated, and subjected to functional studies, which showed a minor but potentially relevant effect in vitro. This cell line offers the possibility to study further the role of chromosome 21 in ALL.

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Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Abstract: Purpose: Children with Down syndrome (DS, constitutive trisomy 21) that develop acute lymphoblastic leukemia (DS-ALL) have a 3-fold increased likelihood of treatment-related

Cited by 19 publications

References 56 publications

RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia

RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia

DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3

The impact of an additional copy of chromosome 21 in B‐cell precursor acute lymphoblastic leukemia

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