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Selective targeting in leukemic stem cells through modulation of selenoprotein biosynthesis by PSTK [RNA-Seq]

ABSTRACT: Despite the genetic heterogeneity in acute myeloid leukemia (AML), a common feature is the arrest of leukemic myeloblasts at an immature, self-renewing stage, with distinct metabolic processes, rendering them susceptible to oxidative stress compared to normal hematopoietic cells. Modulating metabolic pathways emerges as a promising therapeutic approach, particularly post-chemotherapy relapse. Phenotypic CRISPR-Cas9 screening identified phosphoseryl-tRNA kinase (PSTK), an atypical enzyme in the selenoprotein biosynthesis, as an AML differentiation blocker and a broad anti-cancer target. In vivo study demonstrated PSTK’s indispensable role in sustaining leukemic stem cell self-renewal and initiating of leukemia. Pharmacologic PSTK inhibition effectively targeted chemo-resistant AML in mice and patient-derived xenograft (PDX) models, with a discernible preference for malignant cell over normal blood cells. Mechanistically, PSTK inhibition induced reactive oxygen species (ROS)-mediated oxidative stress, mitochondrial damage and eventual engagement of the cGAS-STING pathway and ROS regulation loop, culminating in ferroptosis. These findings highlight the dependency of leukemia cells to selenoprotein biosynthesis pathway and advocate for PSTK modulation as a precise and timed therapeutic strategy for AML, preserving hematopoietic stem cell (HSC) functionality.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263608 | GEO | 2026/05/20

REPOSITORIES: GEO

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Selective targeting in leukemic stem cells through modulation of selenoprotein biosynthesis by PSTK

Project description:Despite the genetic heterogeneity in acute myeloid leukemia (AML), a common feature is the arrest of leukemic myeloblasts at an immature, self-renewing stage, with distinct metabolic processes, rendering them susceptible to oxidative stress compared to normal hematopoietic cells. Modulating metabolic pathways emerges as a promising therapeutic approach, particularly post-chemotherapy relapse. Phenotypic CRISPR-Cas9 screening identified phosphoseryl-tRNA kinase (PSTK), an atypical enzyme in the selenoprotein biosynthesis, as an AML differentiation blocker and a broad anti-cancer target. In vivo study demonstrated PSTK’s indispensable role in sustaining leukemic stem cell self-renewal and initiating of leukemia. Pharmacologic PSTK inhibition effectively targeted chemo-resistant AML in mice and patient-derived xenograft (PDX) models, with a discernible preference for malignant cell over normal blood cells. Mechanistically, PSTK inhibition induced reactive oxygen species (ROS)-mediated oxidative stress, mitochondrial damage and eventual engagement of the cGAS-STING pathway and ROS regulation loop, culminating in ferroptosis. These findings highlight the dependency of leukemia cells to selenoprotein biosynthesis pathway and advocate for PSTK modulation as a precise and timed therapeutic strategy for AML, preserving hematopoietic stem cell (HSC) functionality.

2026-05-20 | GSE263610 | GEO

PLCG1 is required for AML1-ETO leukemia stem cell self-renewal

Project description:In an effort to identify novel drugs targeting fusion-oncogene induced acute myeloid leukemia (AML), we performed high-resolution proteomic analysis. In AML1-ETO (AE) driven AML we uncovered a deregulation of phospholipase C (PLC) signaling. We identified PLCgamma 1 (PLCG1) as a specific target of the AE fusion protein which is induced after AE binding to intergenic regulatory DNA elements. Genetic inactivation of PLCG1 in murine and human AML inhibited AML1-ETO dependent self-renewal programs, leukemic proliferation, and leukemia maintenance in vivo. In contrast, PLCG1 was dispensable for normal hematopoietic stem- and progenitor cell function. These findings are extended to and confirmed by pharmacologic perturbation of Ca++-signaling in AML1-ETO AML cells, indicating that the PLCG1 pathway poses an important therapeutic target for AML1-ETO positive leukemic stem cells.

2021-11-04 | PXD026374 | Pride

AML1-ETO induced leukemia stem cell self-renewal depends on Plcg1

Project description:High-resolution proteomic analysis of acute myeloid leukemia (AML) stem cells identified phospholipase C- and Ca++-signaling pathways to be differentially regulated in AML1-ETO (AE) driven leukemia. Phospholipase C gamma 1 (Plcg1) could be identified as a direct target of the AE fusion. Genetic Plcg1 inactivation abrogated disease initiation by AE, reduced intracellular Ca++-release and inhibited AE-driven self-renewal programs. In AE-induced leukemia, Plcg1 deletion significantly reduced disease penetrance, number of leukemia stem cells and abrogated leukemia development in secondary recipient hosts. In human AE-positive leukemic cells inactivation of Plcg1 reduced colony formation and AML development in vivo. In contrast, Plcg1 was dispensable for maintenance of murine and human hematopoietic stem- and progenitor cells (HSPCs). Pharmacologic inhibition of Ca++-signaling downstream of Plcg1 resulted in impaired proliferation and self-renewal capacity in AE-driven AML. Thus, the Plcg1 pathway represents a novel specific vulnerability of AE-driven leukemia and poses an important new therapeutic target.

2022-01-12 | PXD011251 | Pride

CKS1-dependent proteostatic regulation has dual roles in combating acute myeloid leukemia whilst protecting normal hematopoiesis

Project description:Acute myeloid leukemia (AML) is an aggressive hematological disorder comprised of a hierarchy of quiescent leukemic stem cells and fast proliferating blasts with limited self-renewal ability. Significant plasticity in the AML epigenome and metabolome results in a high rate of drug resistance and relapse, with extremely low 2-year survival rates in the poorest cytogenetic risk patients. The current backbone of clinical induction chemotherapy reduces total disease burden, but does not deplete leukemic stem cells which reconstitute the disease in vivo, and also suffers from severe toxicity of healthy hematopoietic cells. Whilst much work has been done to identify epigenetic vulnerabilities in AML, little is known about protein dynamics, and here we explored the therapeutic inhibition of highly specific CKS1-dependent protein degradation. We report a dual role for CKS1-depdent protein degradation in specifically targeting AML, whilst protecting normal hematopoietic cells from chemotherapeutic toxicity.

2022-07-20 | PXD022754 | Pride

Hematopoietic cell differentiation is required for initiation of acute myeloid leukemia [Microarray expression]

Project description:Leukemia initiating cells (LICs) of acute myeloid leukemia (AML) may arise from self-renewing hematopoietic stem cells (HSCs) and from committed progenitors. However, it remains unclear how leukemia-associated oncogenes instruct LIC formation from cells of different origins and if differentiation along the normal hematopoietic hierarchy is involved. Here, using murine models with the driver mutations MLL-AF9 or MOZ-TIF2, we found that regardless of the transformed cell types, myelomonocytic differentiation to the granulocyte macrophage progenitor (GMP) stage is critical for LIC generation. Blocking myeloid differentiation through disrupting the lineage-restricted transcription factor C/EBPa eliminates GMPs, blocks normal granulopoiesis, and prevents AML development. In contrast, restoring myeloid differentiation through inflammatory cytokines “rescues” AML transformation. Our findings identify myeloid differentiation as a critical step in LIC formation and AML development, thus guiding new therapeutic approaches. Primary KSL, CMP, and GMP cells from wildtype controls and C/Ebpa knockouts were used for RNA extraction and hybridization on Affymetrix microarrays. We also compared the microarray samples of leukemic granulocyte macrophage progenitor compartments (L-GMPs) from MLL-AF9 transformed control or cytokine rescued C/EBPa KO leukemic mouse bone marrow and their secondary recipients with those non-Leukemia KSLs and CMPs from MLL-AF9 transduecd KO recipients with no leukemia development.

2015-08-04 | E-GEOD-71687 | biostudies-arrayexpress

Hematopoietic cell differentiation is required for initiation of acute myeloid leukemia

2014-09-17 | E-GEOD-61468 | biostudies-arrayexpress

Upregulated heme biosynthesis, an exploitable vulnerability in MYCN-driven leukemogenesis

Project description:The increased heme biosynthesis long observed in leukemia was previously of unknown significance. Heme, synthesized from porphyrin precursors, plays a central role in oxygen metabolism and mitochondrial function, yet little is known about its role in leukemogenesis. Here we show increased expression of heme biosynthetic genes, including UROD, only in pediatric AML with high MYCN expression. Both high UROD and MYCN expression predict poor overall survival and unfavorable outcomes in adult AML. Murine leukemic progenitors derived from hematopoietic progenitor cells (HPCs) overexpressing a MYCN cDNA (MYCN-HPC) require heme/porphyrin biosynthesis, accompanied by increased oxygen consumption, to fully engage in self-renewal and oncogenic transformation. Blocking heme biosynthesis reduced mitochondrial oxygen consumption and markedly suppressed self-renewal. Leukemic progenitors rely on balanced production of heme and heme intermediates, the porphyrins. Porphyrin homeostasis is required because absence of the porphyrin exporter, ABCG2, increased death of leukemic progenitors in vitro and prolonged the survival of mice transplanted with Abcg2-KO MYCN HPCs. Pediatric AML patients with elevated MYCN mRNA display strong activation of TP53 target genes. Abcg2-KO MYCN HPCs were rescued from porphyrin toxicity by p53 loss. This vulnerability was exploited to show that treatment with a porphyrin precursor, coupled with the absence of ABCG2, blocked MYCN-driven leukemogenesis in vivo thereby demonstrating, that porphyrin homeostasis is a pathway crucial to MYCN leukemogenesis. We used microarrays to compare the global transcription profiles of hematopoietic progenitor cells from wild-type and Abcg2-ko mice that after transduction with vector-alone or vector containing MYCN gene.

2020-01-10 | GSE100437 | GEO

In vivo CRISPR screening unveils RNA binding protein dependencies for leukemic stem cells and identifies ELAVL1 as a potential therapeutic target [eCLIPseq]

Project description:RNA binding protein (RBP)-directed post-transcriptional control of stem cell fate represents an underexplored mechanism driving hematopoietic stemness and transformation. We show that a unique set of RBPs are specifically enriched in leukemic stem cells (LSCs) of human primary acute myeloid leukemia (AML) but repressed in normal hematopoietic stem cells. Using an in vivo CRISPR-Cas9-mediated screening approach, we identify 33 key RBPs specifically essential for LSC-mediated MLL-AF9/NrasG12D AML. Knock-down/genetic ablation of the hit RBP Elavl1 in genetically distinct leukemias significantly reduced LSC numbers, and hampered leukemic engraftment. In human AML we show impairment of LSC-driven in vivo leukemic reconstitution and selective depletion of AML progenitors upon ELAVL1 targeting, highlighting the potential clinical importance of our findings. Profiling of the leukemic ELAVL1-mRNA interactome revealed hematopoietic differentiation, RNA splicing and mitochondrial metabolism as major pathways impacted by ELAVL1. Altogether, this work demonstrates that Elavl1 and other RBPs are critical regulators of LSC-survival and self-renewal.

2023-01-18 | GSE127944 | GEO

In vivo CRISPR screening unveils RNA binding protein dependencies for leukemic stem cells and identifies ELAVL1 as a potential therapeutic target [RNA-seq]

2023-01-18 | GSE127743 | GEO

A two-step in vivo CRISPR screen unveils pervasive RNA binding protein dependencies for leukemic stem cells and identifies ELAVL1 as a therapeutic target

Project description:Acute myeloid leukemia (AML) progression and relapse is fueled by self-renewing leukemic stem cells (LSCs) whose molecular determinants have been difficult to discern from normal hematopoietic stem cells (HSCs) or to uncover in screening approaches focused on general AML cell properties. We have identified a unique set of RNA binding proteins (RBPs) that are enriched in human AML LSCs but repressed in HSCs. Using an in vivo two step CRISPR-Cas9-mediated screening approach to specifically score for cancer stem cell functionality, we found 32 RBPs essential for LSC propagation and self- renewal in MLL-AF9 translocated AML. Using knockdown or small molecule approaches we show that targeting key hit RBP ELAVL1 impaired LSC-driven in vivo leukemic reconstitution and selectively depleted primitive AML cells vs. normal hematopoietic stem and progenitors. Importantly, knockdown of Elavl1 spared HSCs while significantly reducing LSC numbers across genetically diverse leukemias. Integrative RNA-seq and eCLIP-seq profiling revealed hematopoietic differentiation, RNA splicing and mitochondrial metabolism as key features defining the leukemic ELAVL1-mRNA interactome with the mitochondrial import protein TOMM34 being a direct ELAVL1-stabilized target whose inhibition impairs AML propagation.

2023-03-13 | GSE224548 | GEO

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