Biology subjects

Larrue, C.

Publications and source records attributed to Larrue, C..

3 recordsLinked to original sources

bioRxiv2020

An in vivo CRISPR screening platform for prioritizing therapeutic targets in AML

CRISPR-Cas9-based genetic screens have successfully identified cell type-dependent liabilities in cancers, including acute myeloid leukemia (AML), a devastating hematologic malignancy with poor overall survival. Because most of these screens have been performed in vitro, evaluating the physiological relevance of these targets is critical. We have established a CRISPR screening approach using orthotopic xenograft models to prioritize AML-enriched dependencies in vivo, complemented by the validation in CRISPR-competent AML patient-derived xenograft (PDX) models tractable for genome editing. Our integrated pipeline has revealed several targets with translational value, including SLC5A3 as a metabolic vulnerability for AML addicted to exogenous myo-inositol and MARCH5 as a critical guardian to prevent apoptosis in AML. MARCH5 repression enhanced the efficacy of BCL2 inhibitors such as venetoclax, highlighting the clinical potential of targeting MARCH5 in AML. Our study provides a valuable strategy for discovery and prioritization of new candidate AML therapeutic targets. Statement of significanceThere is an unmet need to improve the clinical outcome of AML. We developed an integrated in vivo screening approach to prioritize and validate AML dependencies with high translational potential. We identified SLC5A3 as a metabolic vulnerability and MARCH5 as a critical apoptosis regulator in AML, representing novel therapeutic opportunities.

cancer biology↗

bioRxiv2020

Adrenomedullin-CALCRL Axis Controls Relapse-Initiating Drug Tolerant Acute Myeloid Leukemia Cells

Drug tolerant leukemic cell subpopulations may explain frequent relapses in acute myeloid leukemia (AML), suggesting that these Relapse-Initiating Cells (RICs) persistent after chemotherapy represent bona fide targets to prevent drug resistance and relapse. We uncovered that the G-protein coupled receptor CALCRL is expressed in leukemic stem cells (LSCs) and RICs, and that the overexpression of CALCRL and/or of its ligand adrenomedullin (ADM) and not CGRP correlates to adverse outcome in AML. CALCRL knockdown impairs leukemic growth, decreases LSC frequency and sensitizes to cytarabine in patient-derived xenograft (PDX) models. Mechanistically, the ADM-CALCRL axis drives cell cycle, DNA repair and mitochondrial OxPHOS function of AML blasts dependent on E2F1 and BCL2. Finally, CALCRL depletion reduces LSC frequency of RICs post-chemotherapy in vivo. In summary, our data highlight a critical role of ADM-CALCRL in post-chemotherapy persistence of these cells, and disclose a promising therapeutic target to prevent relapse in AML.

cancer biology↗

bioRxiv2020

Mitochondrial determinants of response and resistance to venetoclax plus cytarabine duplet therapy in acute myeloid leukemia

The development of resistance to conventional and targeted therapy represents a major clinical barrier in treatment of acute myeloid leukemia (AML). We show that the resistance to cytarabine (AraC) and its associated mitochondrial phenotype were reversed by genetic silencing or pharmacological inhibition of BCL2 in a caspase-dependent manner. BCL2-inhibitor venetoclax (VEN) enhancement of AraC efficacy was independent of differentiation phenotype, a characteristic of response to another combination of VEN with hypomethylating agents (HMA). Furthermore, transcriptional profiles of patients with low response to VEN+AraC mirrored those of low responders to VEN+HMA in clinical trials. OxPHOS was found to be a patient stratification marker predictive of effective response to VEN+AraC but not to VEN+AZA. Importantly, whereas three cell subpopulations specifically emerged in VEN+AraC residual disease and were characterized by distinct developmental and transcriptional programs largely driven by MITF, E2F4 and p53 regulons, they each encoded proteins involved in assembly of NADH dehydrogenase complex. Notably, treatment of VEN+AraC-persisting AML cells with an ETCI inhibitor significantly increased the time-to-relapse in vivo. These findings provide the scientific rationale for new clinical trials of VEN+AraC combinations, especially in patients relapsing or non-responsive to chemotherapy, or after failure of frontline VEN+HMA regimen.

cancer biology↗