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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

Defective ribosome assembly impairs leukemia progression in a murine model of acute myeloid leukemia

Project description:Despite the advanced understanding of disease mechanisms, the current therapeutic regimens fail to cure most patients with acute myeloid leukemia (AML). In the present study, we address the role of protein synthesis control in AML leukemia stem cell (LSC) function and leukemia propagation. We apply a murine model of mixed-lineage leukemia-rearranged AML to demonstrate that LSCs synthesize more proteins per hour compared with the bulk of leukemia. Using a genetic model that permits inducible and graded regulation of ribosomal subunit joining, we show that defective ribosome assembly leads to a significant survival advantage by selectively eradicating LSCs but not normal hematopoietic stem and progenitor cells. Finally, transcriptomic and proteomic analyses identify a rare subset of LSCs with immature stem cell signature and high ribosome content that underlies the resistance to defective ribosome assembly. Collectively, our study unveils a critical requirement of high protein synthesis rate for LSC function, highlighting ribosome assembly as a therapeutic target in AML.

2024-10-08 | PXD038318 | Pride

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

Project description:Acute myeloid leukemia (AML) is a highly heterogeneous disease and reliable detection of leukemic stem cells (LSCs) across genetic subclasses has proven difficult. We aimed to transcriptionally characterize LSCs specifically in monocyte-like AML (Mono-AML) and and primitive-like AML (Prim-AML) samples using cell surface markers. We used CD64+CD11b+ to define Mature blasts and labelled the rest as Immature. To further enrich for LSC-like cells in the Immature blasts in both Mono- and Prim-AML samples, we included GPR56, a marker for LSCs. We performed RNA sequencing on the FACS-sorted LSC-like and Mature cells from 23 AML patients.

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

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