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Only hematopoietic stem and progenitor cells from cord blood are susceptible to malignant transformation by MLL-AF4 translocations

ABSTRACT: MLL rearrangements (MLLr) play a crucial role in leukemogenesis. Dependent on age, major differences exist regarding disease frequency, main fusion partners and prognosis. In infants, up to 80% of acute lymphoid leukemia (ALL) bear t(4;11) resulting in a poor prognosis. In contrast, in adults only 10% of acute myeloid leukemia (AML) bear t(9;11) with an intermediate prognosis. The reasons for these differences are only poorly understood. Recently, we established an efficient human patient-specific CRISPR/Cas9-based MLLr model in hematopoietic stem and progenitor cells (HSPCs) derived from human cord blood (huCB) faithfully mimicking the underlying biology of the disease. Here, we transfer this model into an adult system using HSPCs from adult bone marrow (huBM) allowing us to investigate the impact of the cell of origin and fusion partner on disease development. RNA-Seq uncovered an absent downregulation of FFAR2 in t(4;11) huBM, an epigenetic tumor suppressor, potentially responsible for the inability of MLL-AF4 to immortalize adult cells under myeloid conditions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148714 | GEO | 2020/07/20

REPOSITORIES: GEO

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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

Quantitative analysis of redox proteome reveals protein thiol switches regulating fundamental processes in developmental haematopoiesis

Project description:Foetal and adult hematopoietic stem and progenitor cells (HSPCs) are characterized by distinct redox homeostasis that may influence their differential cellular behaviour in normal and malignant haematopoiesis. In this work, we have applied a quantitative mass spectrometry-based redox proteomic approach to comprehensively describe reversible cysteine modifications in primary mouse foetal and adult HSPCs. We defined the redox state of 4455 cysteines in foetal and adult HSPCs and demonstrated a higher susceptibility to oxidation of protein thiols in foetal HSPCs. Our data identified ontogenically active redox switches in proteins with a pronounced role in metabolism and protein homeostasis. Additional redox proteomic analysis identified redox switches acting in mitochondrial respiration as well as protein homeostasis to be triggered during onset of MLL-ENL leukemogenesis in foetal HSPCs. Our data has demonstrated that redox signalling contributes to the regulation of fundamental processes of developmental haematopoiesis and has pinpointed potential targetable redox-sensitive proteins in in utero-initiated MLL-rearranged leukaemia.

2022-06-09 | PXD030043 | Pride

Quantitative analysis of redox proteome reveals protein thiol switches regulating fundamental processes in developmental hematopoiesis

Project description:Fetal and adult hematopoietic stem and progenitor cells (HSPCs) are characterized by distinct redox homeostasis that may influence their differential cellular behaviour in normal and malignant haematopoiesis. In this work, we have applied a quantitative mass spectrometry-based redox proteomic approach to comprehensively describe reversible cysteine modifications in primary mouse fetal and adult HSPCs. We defined the redox state of 4455 cysteines in fetal and adult HSPCs and demonstrated a higher susceptibility to oxidation of protein thiols in fetal HSPCs. Our data identified ontogenically active redox switches in proteins with a pronounced role in metabolism and protein homeostasis. Additional redox proteomic analysis identified redox switches acting in mitochondrial respiration as well as protein homeostasis to be triggered during onset of MLL-ENL leukemogenesis in fetal HSPCs. Our data has demonstrated that redox signalling contributes to the regulation of fundamental processes of developmental hematopoiesis and has pinpointed potential targetable redox-sensitive proteins in in utero-initiated MLL-rearranged leukaemia. An H9 human embryonic stem cells cell line was applied to validate data from the primary cells.

2022-06-09 | PXD033115 | Pride

Quantitative secretome analysis of fetal and adult hematopoietic progenitors during leukemia initiation and its response to Fibulin and/or Fibronectin treatment.

Project description:We describe the proteomic composition of the secretome of fetal and adult hematopoietic progenitors during MLL-rearranged (MLLr) leukemia initiation as well as the pre-leukemic cells’ secretion response to the treatment with Fibulin (Fbln1) and/or Fibronectin (Fn1) using data-independent acquisition mass spectrometry analysis.

2024-04-02 | PXD049014 | Pride

MLL-rearranged acute lymphoblastic leukemias upregulate BCL-2 through H3K79 methylation and are highly sensitive to the BCL-2 specific antagonist ABT-199

Project description:We present ChIP-seq in the t(4;11) cell line SEM for different components of the MLL-AF4 complex as well as other chromatin proteins Examination of 5 histone marks, MLL, AF4, ENL and CFP1 in t(4;11) cells

2015-12-17 | E-GEOD-74812 | biostudies-arrayexpress

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Project description:Epigenetic dysregulation plays a pivotal role in MLL pathogenesis, therefore serving as suitable therapeutic point of attack. SAM is the universal methyl donor in human cells and is synthesized by MAT2A. MAT2A is already known to be deregulated in different cancer types. Here, we used our human CRISPR/Cas9-MLLr leukemia model, faithfully mimicking MLL patients’ pathology with indefinite growth potential in in vitro culture, to evaluate the unknown role of MAT2A as therapeutic target. Comparable to publicly available patient data, we detected MAT2A to be significantly overexpressed in our CRISPR/Cas9-MLLr model compared to healthy controls. By using non-MLLr and MLLr cell lines and our model, we detected an MLLr specific enhanced response to PF-9366, a new MAT2A inhibitor, by alteration of proliferation, viability, differentiation, apoptosis and cell cycling. Moreover, the combinational treatment of PF-9366 with chemotherapy or targeted therapies against the SAM-dependent methyltransferases DOT1L and PRMT5, revealed even more pronounced effects. In summary, we uncovered MAT2A as a key regulator in MLL leukemogenesis and its inhibition led to significant anti-leukemic effects. Therefore, our study paves the avenue for clinical application of PF-9366 to improve the treatment of poor prognosis MLLr leukemia.

2020-06-22 | GSE141839 | GEO

Transcription profling of infants (<1 year of age) diagnosed with Acute Lymphoblastic Leukemia (ALL) characterised by genomic translocation.

Project description:Acute Lymphoblastic Leukemia (ALL) in infants (<1 year) is characterized by a poor prognosis and a high incidence of MLL translocations. Several studies demonstrated the unique gene expression profile associated with MLL-rearranged ALL, but generally small cohorts were analyzed as uniform patient groups regardless of the type of MLL translocation, while the analysis of translocation-negative infant ALL remained unacknowledged. We generated and analyzed primary infant ALL expression profiles (n=73) typified by translocations t(4;11), t(11;19) and t(9;11), or the absence of MLL translocations, in order to study translocation-specific gene expression between the different genetic subtypes of infant ALL.

2009-12-15 | E-GEOD-19475 | biostudies-arrayexpress

Instructive role of MLL fusion proteins revealed by a faithful model of t(4;11) proB acute lymphoblastic leukemia

Project description:The t(4;11)(q21;q23) fuses MLL to AF4, the most common MLL fusion partner. Here we show that MLL fused to murine Af4, highly conserved with human AF4, produces high-titer retrovirus permitting efficient transduction of human CD34+ cells to generate a faithful model of t(4;11) proB ALL that fully recapitulates the immunophenotypic and molecular aspects of the disease. MLL-Af4 induces a distinct B-ALL from MLL-AF9 through differential DNA binding of the fusion proteins leading to specific gene expression patterns. MLL-Af4 cells can assume a myeloid state under environmental pressure but retain lymphoid-lineage potential. We observed this incongruity in t(4;11) patients who evaded CD19-directed therapy by undergoing myeloid-lineage switch. Our model provides a valuable tool to unravel the pathogenesis of MLL-AF4 leukemogenesis.

2016-11-23 | GSE84116 | GEO

Three-dimensional chromatin landscapes in MLLr AML [Micro-C]

Project description:Rearrangements of the mixed lineage leukemia (MLLr) gene are frequently associated with both pediatric and adult leukemia. However, the treatment options for these aggressive MLLr leukemias are limited due to the genomic complexity and dynamics of 3D structure in oncogene transcription and leukemia development. Here, we use Micro-C and transcriptome profiling to examine the MLLr-driven aberrant 3D genome architecture in gene-edited MLL-AF9 AML samples with biologically matched healthy donors. Recurrent and MLLr-specific alterations in A/B compartments, topologically associating domains and chromatin loops were identified. RNA sequencing in the same AML samples also revealed extensive and recurrent MLLr-specific promoter–enhancer and promoter–silencer loops. Overall, this study highlights the critical regulatory elements and provides rational and effective targeting strategy in MLLr AML.

2024-02-20 | GSE244471 | GEO

Three-dimensional chromatin landscapes in MLLr AML [RNA-Seq]

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