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Targeting mitochondrial apoptotic priming state to personalize therapy for relapsed acute myeloid leukemia

ABSTRACT: The majority of relapsed acute myeloid leukemia (AML) patients still succumb to disease despite improvements in therapy. We present landscapes of pharmacologic sensitivity for 22 AML patient-derived xenograft (PDX) models together with genomic and transcriptomic profiles. First, we used ex vivo dynamic BH3 profiling (DBP) to segregate PDXs according to prior treatment status and accurately predicted in vivo efficacy of drugs with varying mechanisms of action. We next selected in vivo acquired resistance to single agents of distinct mechanisms, which caused broad chemoresistance across all models associated with a reduction in mitochondrial apoptotic priming. DBP could identify drugs with persistent in vivo activity even in these resistant models. Using RNA-seq, we found conserved gene expression signatures defining relapsed phenotypes common to mechanistically distinct agents targeting FLT-3, BCL2, IAPs, and BRD-4. We replicated drug-response patterns from PDX models in primary and relapsed AML patients, demonstrating the clinical feasibility of such approach

ORGANISM(S): Mus musculus

PROVIDER: GSE237794 | GEO | 2024/02/15

REPOSITORIES: GEO

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Alkynyl nicotinamides with antileukemic activity to treat poor prognosis AM

Project description:FLT3 activating mutations cause myeloproliferative neoplasms by deregulating hematopoietic progenitor cell growth, and acute myeloid leukemia is on the rise. Investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop inherent and acquired resistance to FLT3 targeted therapy. FLT3 inhibitor resistance in AML is dependent on co-occurring mutations, parallel survival pathways, and/or subsequent FLT3-ITD mutations. Despite the high prevalence of FLT3 mutations and their clinical significance in AML, there are few targeted therapeutic options. We identified two novel naphthyridine-based FLT3 inhibitors (HSN608 and HSN748) that specifically target FLT3-ITD at sub-nanomolar concentrations and are effective against drug-resistant secondary mutations. In the current study, we evaluated these compounds antileukemic activity against FLT3-ITD and gatekeeper mutations in drug-resistant AML, relapsed/refractory AMLs with FLT3 mutations, and in vivo mouse models with combinations of epigenetic mutations TET2 with FLT3-ITD, and AML patients PDX. In these model systems, we demonstrate that HSN748 outperforms the FDA-approved FLT3 inhibitor Gilteritinib in terms of inhibitory activity against FLT3-ITD.

2022-12-07 | MSV000090855 | MassIVE

Differential gene expression analysis of pediatric acute myeloid leukemia cell lines treated with azacytidine and panobinostat alone or in combination and compared to vehicle treated cells.

Project description:Pediatric AML cell lines (MV4;11, AML-193 and THP-1) were treated with DNA hypomethylating agent (azacytidine) and a pan histone deactylase inhibitor (panobinostat) alone or in combination. Treatment of AML cell lines with these epigenetic drugs synergistically suppresses cell viability in vitro and in xenograft models in vivo. Data show differential regulation of gene expression in AML cell lines by epigenetic drugs at concentrations which retained cell viability at a minimum of 75% even in the combination treatment.

2017-07-01 | GSE83983 | GEO

scRNA seq data from AML PDXs throughout a cytarabine treatment, and directly from AML patients at differnet stages of disease progression

Project description:We used scRNA seq on regenerating PDX models and de novo AML patient cells to delineate the heirarchical regeneration of AML following treatment

2024-04-05 | GSE255245 | GEO

Adverse stem cell features in a single AML sample predict clinical outcome in AML patient cohorts

Project description:Patients with acute myeloid leukemia (AML) suffer dismal prognosis and the most adverse subpopulation within each tumor determines patient’s prognosis. To better understand challenging features in AML, we studied individual stem cells from a single AML sample, complementing genomic with in vivo functional studies. Primary tumor cells from an AML patient’s first and second relapse were transplanted into NSG mice to establish serially transplantable patient derived xenografts (PDX). In an innovative approach, twelve derivative PDX clones were generated thereof, each derived from a single AML stem cell as proven by molecular barcoding, and were color-marked to facilitate multiplex competitive in vivo assays. PDX clones consisted of four different genomic clusters; one cluster displayed resistance against Cytarabine treatment, while two other clusters harbored increased stem cell potential, indicating that stemness and treatment resistance had evolved independently in the sample. In vivo functional data correlated closely with the phylogenetic tree calculated from exome data. The Cytarabine-resistant cluster was characterized by a distinct gene expression profile, and a score thereof predicted outcome in large clinical patient data cohorts. Taken together, we provide proof of concept that intra-sample heterogeneity mimics inter-sample heterogeneity in AML. Stem cell disparities within a single sample allow insights into adverse characteristics of general importance for AML.

2022-04-04 | PXD026296 | Pride

Functional plasticity and reversible growth behavior of patients’ acute myeloid leukemia stem cells growing in mice

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2020-09-03 | GSE141627 | GEO

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2021-08-30 | GSE178901 | GEO

Discovery of a drug targeting microenvironmental support for lymphoma cells by screening using patient-derived xenograft cells

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2015-08-31 | E-GEOD-71944 | biostudies-arrayexpress

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2020-06-27 | GSE153382 | GEO

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Project description:Somatic mutations are rare in pediatric AML (pAML), indicating alternate strategies are needed to identify new, pediatric AML-specific, druggable targets. We defined the enhancer landscape of 22 pAML patient samples and observed many known leukemia regulators are SE-associated in pAML. The retinoic acid receptor alpha (RARA) gene was differentially regulated in our cohort and present in all cyto/molecular subtypes tested, totaling 64% of the pAML samples. RARA SE-positive pAML cell lines and samples had higher RARA mRNA levels than RARA SE-negative samples and also were specifically sensitive to the synthetic RARA agonist tamibarotene in vitro, with halted proliferation and upregulated retinoid target genes. Tamibarotene prolonged survival and suppressed the leukemia burden of a RARA SE-positive pAML patient-derived xenograft (PDX) mouse model compared to a RARA SE-negative PDX. These data demonstrate the utility of leveraging chromatin regulation to identify new dependencies in pediatric AML and specifically lay the preclinical foundation for a tamibarotene trial in children with relapsed/refractory AML.

2021-08-01 | GSE155558 | GEO

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2023-07-14 | GSE176522 | GEO

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