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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Expression data from PML-RARα transgenic mouse APL(acute promyelocyte leukemia) cells

ABSTRACT: The differentiation of leukemia stem cells (LSCs) is generally regarded as a one-way alterative process to self-renewal. However, how differentiation impacts LSC stemness has largely been unexplored. Here we show that before reaching terminal differentiation (TD), apical LSCs of mouse acute promyelocytic leukemia passed through a partial differentiation (PD) stage, wherein the leukemia cells re-initiated leukemia via de-differentiation albeit at a reduced rate. Notably, while retinoic acid (RA) preferentially drove the transition of LSC to PD, monocytic Irf8 skewed PD cells to terminal maturation over de-differentiation and/or expansion. Remarkably, the combined use of RA and Irf8 induction depleted the total leukemogenic potential, which indicates that discrete stage- or lineage-specific mechanisms elaborate a step-wise LSC differentiation. We used microarrays to detail the global programme of gene expression indicating the molecular mechanisms unerlying the the process of LSC step-wise differentiation. Retroviral GFP-labled mouse APL cells (bone marrow sample) were repopulated in vivo through transplantation into syngenic recipients. At the proper time points, the GFP positive APL bone marrow cells were collected and sorted for UNSC, UNPD and UNTD samples through FACS. RA-PD and RA-TD cells were sorted from bone marrow tissue treated with ATRA (all trans retinoic acid) for 5 days. The freshly isolated samples were then lysed for RNA extration. Each sample had two biological replicates.

ORGANISM(S): Mus musculus

SUBMITTER: Jiang Zhu

PROVIDER: E-GEOD-46094 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression data from PML-RARα transgenic mouse APL(acute promyelocyte leukemia) cells

Project description:The differentiation of leukemia stem cells (LSCs) is generally regarded as a one-way alterative process to self-renewal. However, how differentiation impacts LSC stemness has largely been unexplored. Here we show that before reaching terminal differentiation (TD), apical LSCs of mouse acute promyelocytic leukemia passed through a partial differentiation (PD) stage, wherein the leukemia cells re-initiated leukemia via de-differentiation albeit at a reduced rate. Notably, while retinoic acid (RA) preferentially drove the transition of LSC to PD, monocytic Irf8 skewed PD cells to terminal maturation over de-differentiation and/or expansion. Remarkably, the combined use of RA and Irf8 induction depleted the total leukemogenic potential, which indicates that discrete stage- or lineage-specific mechanisms elaborate a step-wise LSC differentiation. We used microarrays to detail the global programme of gene expression indicating the molecular mechanisms unerlying the the process of LSC step-wise differentiation.

2014-05-01 | GSE46094 | GEO

Leptin secreted from testicular microenvironment modulates hedgehog signaling to augment the endogenous function of Leydig cells

Project description:Although testosterone deficiency (TD) may be present in 1 out of 5 men 40 years or older, the factors responsible for TD remain largely unknown. Leydig stem cells (LSCs) differentiate into adult Leydig cells (ALC) and produce testosterone in the testes under the pulsatile control of luteinizing hormone (LH) from the pituitary gland. However, recent studies have suggested that the testicular microenvironment (TME), which is comprised of Sertoli and peritubular myoid cells (PMC), plays an instrumental role in LSC differentiation and testosterone production under the regulation of the desert hedgehog signaling pathway (DHH). It was hypothesized that TME releases paracrine factors to modulate LSC differentiation. For this purpose, cells (Sertoli, PMCs, LSCs and ALCs) were extracted from men undergoing testis biopsies for sperm retrieval and were evaluated for the paracrine factors in the presence or absence of TME (Sertoli and PMC). The results demonstrated that TME secretes leptin which induces LSC differentiation and increases T production. Leptin’s effects on LSC differentiation and T production, however, are inversely concentration-dependent: positive at low doses and negative at higher doses. Mechanistically, leptin acts on LSCs upstream of DHH; leptin-DHH regulation functions unidirectionally insofar as DHH gain or loss of function has no effects on leptin levels. Taken together, these findings identify leptin as a key paracrine factor released by cells within the TME that modulates LSC differentiation and testosterone release from mature Leydig cells, a finding with important clinical implications for TD.

2022-02-17 | GSE196702 | GEO

Distinct leukemogenic mechanism of acute promyelocytic leukemia based on genomic structure of PML-RARα fusion gene

Project description:Leukemic stem cells (LSCs) of acute myeloid leukemia (AML) are enriched in CD34+CD38- fraction, and self-renewing LSCs hierarchically organize and maintain the AML populations. In acute promyelocytic leukemia (APL), which is driven by PML-RARα fusion genes, the presence of LSCs has long been unidentified, due to the difficulty of efficient reconstitution of human APL in the immunodeficient mice. Here, we show that LSCs of short type isoform APL, subtype of APL defined by different breakpoint of PML gene, concentrate in CD34+CD38- fraction and express T cell immunoglobulin mucin-3 (TIM-3) as in other non-APL AML. Short type APL cells exhibited distinct gene expression signatures including LSCs-related genes from other types of APL. Moreover, CD34+CD38-TIM-3+ short type APL cells efficiently reconstituted huma APL in xenograft models with high penetration, whereas CD34- more differentiated APL cells did not. Furthermore, CD34+CD38-TIM-3+ short type APL cells also reconstituted leukemia in the serial transplantation. Thus, short type APL is showing hierarchically organized by self-renewing APL-LSCs same as in other types of AML. The identification of LSCs in a subset of APL and establishment of efficient patient derived xenograft model would contribute to further understanding of APL leukemogenesis and devising individual treatment for eradication of APL LSCs.

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Targeting the scaffolding role of LSD1 (KDM1A) poises acute myeloid leukemia cells for Retinoic Acid induced differentiation

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2020-05-26 | PXD012954 | Pride

The H3K4-methyl epigenome regulates MLL leukemia stem cell oncogenic potential

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2015-06-26 | E-GEOD-60193 | biostudies-arrayexpress

Msi2 sustains the MLL leukemia stem cell regulatory program

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

Msi2 sustains the MLL leukemia stem cell regulatory program

2015-01-15 | GSE64545 | GEO

The H3K4-methyl epigenome regulates MLL leukemia stem cell oncogenic potential

2015-06-26 | GSE60193 | GEO

RNA-seq of LSC-like, non-LSC and Mature populations from human AML patient samples

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2023-03-01 | E-MTAB-11976 | biostudies-arrayexpress

T-ALL Leukemia Stem Cell “stemness” is Epigenetically Controlled by the Master Regulator PU.1 [bulkRNA]

Project description:Leukemia stem cells (LSCs) are regarded as the origins and key therapeutic targets of leukemia, but limited knowledge is available on the key determinants of LSC “stemness”. Using single cell RNAseq analysis, we identify a master regulator PU.1, whose LSC-specific expression determines the molecular signature and activity of LSC in the Pten-null T-ALL model. Although initiated by PTEN controlled β-catenin activation, PU.1 expression and LSC “stemness” are maintained by a β-catenin-PU.1-TIM-3 feedback loop, independent of the leukemogenic driver mutation. Perturbing any component of this loop, either genetically or pharmacologically, can prevent LSC formation or eradicate existing LSCs. LSCs lose their “stemness” when PU.1 expression is silenced by DNA methylation, which can be reactivated by 5-AZ. Importantly similar regulatory mechanisms are also present in human T-ALLs.

2018-11-17 | GSE115346 | GEO

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