Leukemia reconstitution
            <i>in vivo</i>
            is driven by cells in early cell cycle and low metabolic state

Trentin, Luca; Queudeville, Manon; Eckhoff, Sarah Mirjam; Hasan, Nabiul; Münch, Vera; Boldrin, Elena; Seyfried, Felix; Enzenmüller, Stefanie; Debatin, Klaus‐Michael; Meyer, Lüder Hinrich

doi:10.3324/haematol.2017.167502

Cited by 6 publications

(5 citation statements)

References 50 publications

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“…Consistent with previous findings in precursor B-ALL, a large fraction of stem-like cells persisted in G1 phase and upregulated stem-cell related pathways, such as cell adhesion facilitating the interaction with the stromal environment and resulting in the protection against external factors in the stem-cell niche 13,38 . Moreover, the analysis of recurrent AS revealed an enrichment in such cells in mRNA isoforms potentially impacting the metabolic activity, including those encoding ribosomal proteins (such as RPL27A), and those that are expected to modulate stem-cell induction, including FOS 36 .…”

Section: Discussionsupporting

confidence: 91%

Role of Stem-Like Cells in Chemotherapy Resistance and Relapse in pediatric T Cell Acute Lymphoblastic Leukemia

Costea,

Rauwolf,

Zafferani

et al. 2024

Preprint

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T cell acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia predominantly affecting adolescents and young adults. T-ALL relapses are characterized by chemotherapy resistance, cellular heterogeneity and dismal outcome. To gain a deeper understanding of the cellular heterogeneity and mechanisms driving relapse, we conducted single-cell full-length RNA sequencing of 13 matched pediatric T-ALL patient-derived xenografts (PDX) samples obtained at initial diagnosis and relapse, generating the to date most comprehensive longitudinal single cell study in paired T-ALL samples, along with 5 non-relapsing PDX samples collected at initial diagnosis. This dataset identifies considerable transcriptomic diversity among individual T-ALL cell populations. Notably however, 11 of the 18 patients exhibit a small T-ALL cell subpopulation with a shared set of gene regulatory networks characterized by a common set of active regulons, expression patterns and splice isoforms. This profile involves the upregulation of a stem-like cell signature with enrichment of cell adhesion, and inhibition of the cell cycle and metabolic activity. Comprehensive investigations of these networks identify transcripts enforcing drug resistance through NF-κB expression and TGF-β signaling and of anti-apoptotic T cell signaling. Longitudinal monitoring of these stem-like cells demonstrates this subpopulation to account for only a small proportion of leukemia cells initially with a substantial expansion at relapse suggesting resistance to first line therapy. Chemotherapy resistance is functionally corroborated throughin vitroandin vivodrug testing. We thus report the discovery of inherently treatment-resistant stem-like T-ALL cell populations underscoring the potential for devising future therapeutic strategies aimed at targeting stemness pathways in pediatric T-ALL.Key PointsSingle-cell full-length RNA sequencing reveals dormant, treatment-resistant cells expanding upon T cell acute lymphoblastic leukemia relapse.Stem-like T-ALL cells exhibit a shared gene regulatory network conferring chemotherapy resistance and relapse.

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Section: Discussionsupporting

confidence: 91%

Role of Stem-Like Cells in Chemotherapy Resistance and Relapse in pediatric T Cell Acute Lymphoblastic Leukemia

Costea,

Rauwolf,

Zafferani

et al. 2024

Preprint

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“…Thus, expression of miR-497/195 controls leukemia expansion in vivo, further confirming a tumor-suppressive function of this miRNA cluster in BCP-ALL. In agreement with this data, pdx leukemias characterized by low expression of miR-497/195 show higher frequencies of leukemia-initiating cells 40 (supplemental Table 2).…”

Section: Expression Of Mir-497/195 Is Suppressed By Promoter Methylationsupporting

confidence: 86%

MicroRNA-497/195 is tumor suppressive and cooperates with CDKN2A/B in pediatric acute lymphoblastic leukemia

Boldrin

Gaffo

Niedermayer

et al. 2021

Blood

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We previously identified an association of rapid engraftment of patient-derived leukemia cells transplanted into NOD/SCID mice with early relapse in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In search for the cellular and molecular profiles associated with this phenotype, we investigated the expression of microRNAs (miRNAs) in different engraftment phenotypes and patient outcomes and found high miR-497/195 expression in patient-derived xenograft samples with slow engraftment, derived from patients with favorable outcome. In contrast, epigenetic repression and low expression of these miRNAs was observed in rapidly engrafting samples associated with early relapse. Overexpression of miR-497/195 in patient-derived leukemia cells suppressed in vivo growth of leukemia and prolonged recipient survival. Conversely, inhibition of miR-497/195 led to increased leukemia cell growth. Key cell cycle regulators were downregulated upon miR-497/195 overexpression and we identified CDK4/CCND3-mediated control of G1/S transition as a principal mechanism for the suppression of BCP-ALL progression by miR-497/195. The critical role for miR-497/195-mediated cell cycle regulation was underscored by the finding in an additional independent series of patient samples, showing that high miR-497/195 expression together with a full sequence of CDKN2A/B was associated with excellent outcome, while deletion of CDKN2A/B together with low expression of miR-497/195 was associated with clearly inferior relapse-free survival. These findings point to the cooperative loss of cell cycle regulators as new prognostic factor indicating possible therapeutic targets for pediatric BCP-ALL.

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“…Gene expression was analyzed using Affymetrix U133 Plus 2.0 arrays as described before 53 . Gene-expression data were deposited in the Gene Expression Omnibus database of the National Center for Biotechnology Information (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE123883, GEO series accession number GSE123883).…”

Section: All Xenograft Samplesmentioning

confidence: 99%

Prediction of venetoclax activity in precursor B-ALL by functional assessment of apoptosis signaling

et al. 2019

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Deregulated cell death pathways contribute to leukemogenesis and treatment failure in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Intrinsic apoptosis signaling is regulated by different proapoptotic and antiapoptotic molecules: proapoptotic BCL-2 homology domain 3 (BH3) proteins activate prodeath molecules leading to cellular death, while antiapoptotic molecules including B-cell lymphoma 2 (BCL-2) prevent activation of prodeath proteins and counter-regulate apoptosis induction. Inhibition of these antiapoptotic regulators has become a promising strategy for anticancer treatment, but variable anticancer activities in different malignancies indicate the need for upfront identification of responsive patients. Here, we investigated the activity of the BCL-2 inhibitor venetoclax (VEN, ABT-199) in B-cell precursor acute lymphoblastic leukemia and found heterogeneous sensitivities in BCP-ALL cell lines and in a series of patient-derived primografts. To identify parameters of sensitivity and resistance, we evaluated genetic aberrations, gene-expression profiles, expression levels of apoptosis regulators, and functional apoptosis parameters analyzed by mitochondrial profiling using recombinant BH3-like peptides. Importantly, ex vivo VEN sensitivity was most accurately associated with functional BCL-2 dependence detected by BH3 profiling. Modeling clinical application of VEN in a preclinical trial in a set of individual ALL primografts, we identified that leukemia-free survival of VEN treated mice was precisely determined by functional BCL-2 dependence. Moreover, the predictive value of ex vivo measured functional BCL-2 dependence for preclinical in vivo VEN response was confirmed in an independent set of primograft ALL including T- and high risk-ALL. Thus, integrative analysis of the apoptosis signaling indicating mitochondrial addiction to BCL-2 accurately predicts antileukemia activity of VEN, robustly identifies VEN-responsive patients, and provides information for stratification and clinical guidance in future clinical applications of VEN in patients with ALL.

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Leukemia reconstitution in vivo is driven by cells in early cell cycle and low metabolic state

Cited by 6 publications

References 50 publications

Role of Stem-Like Cells in Chemotherapy Resistance and Relapse in pediatric T Cell Acute Lymphoblastic Leukemia

Role of Stem-Like Cells in Chemotherapy Resistance and Relapse in pediatric T Cell Acute Lymphoblastic Leukemia

MicroRNA-497/195 is tumor suppressive and cooperates with CDKN2A/B in pediatric acute lymphoblastic leukemia

Prediction of venetoclax activity in precursor B-ALL by functional assessment of apoptosis signaling

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