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The functional role of Musashi-2 uncovers targetable metabolic vulnerabilities of MLL-rearranged infant ALL [RIPchip]

ABSTRACT: MLL-rearranged B-cell Acute Lymphoblastic Leukemia (MLLr B-ALL) is a rare but very aggressive disease frequently occurring in infants and associated with poor outcome. MLLr ALL cells are typically resistant to conventional therapy and prone to relapse. The biological mechanisms involved in the pathogenesis and drug resistance of MLLr ALL are not completely understood and identification of druggable genes is urgently needed to develop novel therapeutic strategies. Here, we found that the RNA-binding protein Musashi-2 (MSI2) plays a crucial role in MLLr B-ALL by sustaining the growth and the leukemogenic potential of MLL::AF4+ ALL cells. In addition, MSI2 is involved in resistance to Glucocorticoids, as the lack or the pharmacological inhibition of MSI2 prevents mitochondrial activation upon Glucocorticoid’s exposure and impairs mitochondrial respiration. The putative role of MSI2 in the bioenergetic metabolism of leukemia is a novel finding that paves the way for targeting metabolic vulnerabilities of B-ALL. The identification of novel therapeutic approaches for MLLr infant ALL remains an unmet need. We demonstrated the fundamental role of MSI2 in the maintenance and treatment resistance of MLLr infant ALL. We also uncovered the involvement of MSI2 in mitochondrial metabolism, paving the way for targeting metabolic vulnerabilities of leukemia

ORGANISM(S): Homo sapiens

PROVIDER: GSE235720 | GEO | 2026/03/06

REPOSITORIES: GEO

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The functional role of Musashi-2 uncovers targetable metabolic vulnerabilities of MLL-rearranged infant ALL [GEP]

Project description:MLL-rearranged B-cell Acute Lymphoblastic Leukemia (MLLr B-ALL) is a rare but very aggressive disease frequently occurring in infants and associated with poor outcome. MLLr ALL cells are typically resistant to conventional therapy and prone to relapse. The biological mechanisms involved in the pathogenesis and drug resistance of MLLr ALL are not completely understood and identification of druggable genes is urgently needed to develop novel therapeutic strategies. Here, we found that the RNA-binding protein Musashi-2 (MSI2) plays a crucial role in MLLr B-ALL by sustaining the growth and the leukemogenic potential of MLL::AF4+ ALL cells. In addition, MSI2 is involved in resistance to Glucocorticoids, as the lack or the pharmacological inhibition of MSI2 prevents mitochondrial activation upon Glucocorticoid’s exposure and impairs mitochondrial respiration. The putative role of MSI2 in the bioenergetic metabolism of leukemia is a novel finding that paves the way for targeting metabolic vulnerabilities of B-ALL. The identification of novel therapeutic approaches for MLLr infant ALL remains an unmet need. We demonstrated the fundamental role of MSI2 in the maintenance and treatment resistance of MLLr infant ALL. We also uncovered the involvement of MSI2 in mitochondrial metabolism, paving the way for targeting metabolic vulnerabilities of leukemia

2026-03-06 | GSE235719 | GEO

Quantitative cellular proteome analysis of Fetal- and Adult-Derived MLL-Rearranged Leukemia

Project description:Infant and adult MLL-rearranged (MLLr) leukemia represents a disease with few treatment options and a dismal prognosis. Here, we present an in-depth proteomic characterization of in utero-initiated and adult-onset MLLr leukemia in a mouse model of MLL-ENL-mediated leukemogenesis. We characterize early proteomic events of MLL-ENL-mediated transformation in fetal and adult progenitors.

2024-04-02 | PXD042249 | Pride

Only infant MLL rearranged leukemia is susceptible to an inhibition of PLK-1 by volasertib

Project description:MLL rearranged (MLLr) leukemia is in general characterized by a poor prognosis. Depending on the cell of origin, it can differ in the aggressiveness and the therapy response. For instance, in adults, volasertib blocking Polo-like-Kinase 1 (PLK-1), was well-tolerated, but only with limited success. On the other site, PLK-1 characterizes an infant MLLr signature indicating a potential specific sensitivity. By using our CRISPR/Cas9 MLLr model in hematopoietic stem and progenitor cells (HSPCs), derived from both human cord blood (huCB) and bone marrow (huBM), mimicking exactly the infant and adult patient diseases, we were able to shed light on this phenomenon. PLK-1 was significantly increased in our huCB compared to huBM model and healthy HPSCs, that was underpinned by analyzing infant and adult MLLr leukemia patients. Importantly, the expression height correlated with a functional response. Volasertib induced a significant dose-dependent decrease of proliferation and cell cycle arrest most pronounced in the infant model. Mechanistically, upon volasertib treatment, we uncovered a negative feedback only in the huBM model by compensatory upregulation of PLK-1. Our study emphasizes the importance of the cell of origin in leukemogenesis and provides the rationale to further evaluate volasertib as new therapeutic strategy in infant MLLr leukemia.

2024-12-19 | GSE276639 | GEO

Msi2 sustains the MLL leukemia stem cell regulatory program

Project description:Leukemia stem cells (LSCs) are found in most aggressive myeloid diseases and contribute to therapeutic resistance. Genetic and epigenetic alterations cause a dysregulated developmental program in leukemia. The MSI2 RNA binding protein has been previously shown to predict poor survival in leukemia. We demonstrate that the conditional deletion of Msi2 results in delayed leukemogenesis, reduced disease burden and a loss of LSC function. Gene expression profiling of the Msi2 ablated LSCs demonstrates a loss of the HSC/LSC and an increase in the differentiation program. The gene signature from the Msi2 deleted LSCs correlates with survival in AML patients. MSI2’s maintains the MLL self-renewal program by interacting with and retaining efficient translation of Hoxa9, Myc and Ikzf2. We further demonstrate that shRNA depletion of the MLL target gene Ikzf2 also contributes to MLL leukemia cell survival. Our data provides evidence that MSI2 controls efficient translation of the oncogenic LSC self-renewal program and a rationale for clinically targeting MSI2 in myeloid leukemia. RNA-Seq was performed on sorted c-Kit high leukemic cells from 2 Msi2 -/- and 2 Msi2 f/f mice.

2015-01-15 | E-GEOD-64545 | biostudies-arrayexpress

Msi2 sustains the MLL leukemia stem cell regulatory program

2015-01-15 | GSE64545 | GEO

Heritable fetal protection against MLL::ENL-driven leukemogenesis depends on MLL3 [Bulk RNA-seq]

Project description:MLL rearrangements (MLLr) are the most common cause of congenital and infant leukemias. MLLr arise prior to birth and require very few cooperating mutations for transformation, yet congenital leukemias are 10-fold less common than infant leukemias and >100-fold less common than childhood leukemias overall. This raises the question of whether mechanisms exist to suppress leukemic transformation during fetal life. Here, we show that in mice, fetal MLL::ENL exposure creates a heritable, leukemia-resistant state. MLL::ENL imposes a negative selective pressure on fetal hematopoietic progenitors that persists after birth to suppress transformation. These changes do not occur when MLL::ENL is induced shortly after birth, and transformation proceeds efficiently in that context. The fetal barrier to transformation is enforced by MLL3. It can be bypassed by cooperating mutations or inactivation of MLL3. Heritable, fetal protection against leukemic transformation may explain the low incidence of congenital leukemias in humans despite prenatal MLL rearrangement.

2025-09-19 | GSE291040 | GEO

Heritable fetal protection against MLL::ENL-driven leukemogenesis depends on MLL3 [scATAC-seq]

2025-09-19 | GSE291038 | GEO

Heritable fetal protection against MLL::ENL-driven leukemogenesis depends on MLL3 [scRNA-seq]

2025-09-19 | GSE291037 | GEO

NG2 is a target gene of MLL-AF4 that underlies glucocorticoid resistance in infant MLL-rearranged B-ALL by regulating NR3C1 expression through interaction with FLT3

Project description:B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer, with long-term overall survival rates of 80%. However, B-ALL harboring rearrangements of the MLL gene (also known as KTM2A), hereinafter termed MLLr B-ALL, is frequently seen in infants and is associated with poor 5-year survival (<30%), frequent relapses, and refractoriness to glucocorticoids (GC). GC are an essential part of the treatment backbone for B-ALL and GC resistance is a major clinical predictor of poor outcome. Unraveling the mechanisms of GC resistance in MLLr B-ALL is, therefore, crucial to guide therapeutic strategies that deepen response after induction therapy. Neuron-glial antigen-2 (NG2) expression is a hallmark of MLLr B-ALL and is minimally expressed in healthy hematopoietic cells. We recently reported that NG2 expression is associated with poor prognosis and that anti-NG2 immunotherapy strongly reduces/delays relapse in xenograft models of MLLr B-ALL. However, despite its contribution to MLLr B-ALL pathogenesis and its diagnostic utility, the role of NG2 in MLLr-mediated leukemogenesis/chemoresistance remains elusive. We show here that NG2 is an epigenetically regulated direct target gene of the leukemic MLL-AF4 fusion protein. NG2 negatively regulates the expression of the GC receptor NR3C1, conferring GC chemoresistance to MLLr B-ALL cells in vitro and in vivo. Mechanistically, NG2 interacts with FLT3 to render ligand-independent activation of FLT3 signaling (a hallmark of MLLr B-ALL) and downregulation of NR3C1 via AP-1-mediated transrepression. Collectively, our study elucidates the role of NG2 in GC resistance in MLLr B-ALL through a FLT3/AP-1-mediated downregulation of NR3C1, providing novel therapeutic avenues for MLLr B-ALL.

2024-07-12 | PXD041875 | Pride

In vitro prednisolone resistance signature in MLL-rearranged infant ALL

Project description:Acute Lymphoblastic Leukemia (ALL) in infants (<1 year of age) is characterized by a high incidence of MLL translocations which is associated with a poor prognosis. Contributing to this poor prognosis is cellular drug resistance, especially to glucocorticoids like prednisolone. Although in vitro prednisolone resistance mechanisms have been proposed in pediatric ALL, it has never been studied in MLL-rearranged infant ALL, which are highly resistant to glucocorticoids in vitro and in vivo. We analyzed primary MLL-rearranged infant ALL expression profiles, which were either in vitro prednisolone-resistant or prednisolone-sensitive, in order to study in vitro prednisolone resistance.

2011-10-12 | E-GEOD-32962 | biostudies-arrayexpress

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