scholarly journals RSPO2 inhibits BMP signaling to promote self-renewal in acute myeloid leukemia

Cell Reports ◽  
2021 ◽  
Vol 36 (7) ◽  
pp. 109559
Author(s):  
Rui Sun ◽  
Lixiazi He ◽  
Hyeyoon Lee ◽  
Andrey Glinka ◽  
Carolin Andresen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bmp Signaling ◽  
Self Renewal ◽  
Acute Myeloid

scholarly journals A KDM4A-PAF1-mediated epigenomic network is essential for acute myeloid leukemia cell self-renewal and survival

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Matthew E. Massett ◽  
Laura Monaghan ◽  
Shaun Patterson ◽  
Niamh Mannion ◽  
Roderick P. Bunschoten ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cell Activity ◽  
Leukemia Cell ◽  
Gene Signature ◽  
Pathological Feature ◽  
Self Renewal ◽  
Stem Cell Activity ◽  
Molecular Mechanism Of Action ◽  
Acute Myeloid

AbstractEpigenomic dysregulation is a common pathological feature in human hematological malignancies. H3K9me3 emerges as an important epigenomic marker in acute myeloid leukemia (AML). Its associated methyltransferases, such as SETDB1, suppress AML leukemogenesis, whilst H3K9me3 demethylases KDM4C is required for mixed-lineage leukemia rearranged AML. However, the specific role and molecular mechanism of action of another member of the KDM4 family, KDM4A has not previously been clearly defined. In this study, we delineated and functionally validated the epigenomic network regulated by KDM4A. We show that selective loss of KDM4A is sufficient to induce apoptosis in a broad spectrum of human AML cells. This detrimental phenotype results from a global accumulation of H3K9me3 and H3K27me3 at KDM4A targeted genomic loci thereby causing downregulation of a KDM4A-PAF1 controlled transcriptional program essential for leukemogenesis, distinct from that of KDM4C. From this regulatory network, we further extracted a KDM4A-9 gene signature enriched with leukemia stem cell activity; the KDM4A-9 score alone or in combination with the known LSC17 score, effectively stratifies high-risk AML patients. Together, these results establish the essential and unique role of KDM4A for AML self-renewal and survival, supporting further investigation of KDM4A and its targets as a potential therapeutic vulnerability in AML.

scholarly journals The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9;NrasG12D acute myeloid leukemia

Oncogene ◽  
2012 ◽  
Vol 32 (7) ◽  
pp. 930-938 ◽  
Author(s):  
J Shi ◽  
E Wang ◽  
J Zuber ◽  
A Rappaport ◽  
M Taylor ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mouse Model ◽  
Myeloid Leukemia ◽  
Self Renewal ◽  
Polycomb Complex ◽  
Acute Myeloid

scholarly journals microRNA-29a induces aberrant self-renewal capacity in hematopoietic progenitors, biased myeloid development, and acute myeloid leukemia

2010 ◽  
Vol 207 (3) ◽  
pp. 475-489 ◽  
Author(s):  
Yoon-Chi Han ◽  
Christopher Y. Park ◽  
Govind Bhagat ◽  
Jinping Zhang ◽  
Yulei Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Ectopic Expression ◽  
Hematopoietic Progenitors ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Myeloid Development ◽  
Acute Myeloid ◽  
Myeloid Progenitors

The function of microRNAs (miRNAs) in hematopoietic stem cells (HSCs), committed progenitors, and leukemia stem cells (LSCs) is poorly understood. We show that miR-29a is highly expressed in HSC and down-regulated in hematopoietic progenitors. Ectopic expression of miR-29a in mouse HSC/progenitors results in acquisition of self-renewal capacity by myeloid progenitors, biased myeloid differentiation, and the development of a myeloproliferative disorder that progresses to acute myeloid leukemia (AML). miR-29a promotes progenitor proliferation by expediting G1 to S/G2 cell cycle transitions. miR-29a is overexpressed in human AML and, like human LSC, miR-29a-expressing myeloid progenitors serially transplant AML. Our data indicate that miR-29a regulates early hematopoiesis and suggest that miR-29a initiates AML by converting myeloid progenitors into self-renewing LSC.

scholarly journals A Niche-Like Culture System Allowing the Maintenance of Primary Human Acute Myeloid Leukemia-Initiating Cells: A New Tool to Decipher Their Chemoresistance and Self-Renewal Mechanisms

2014 ◽  
Vol 3 (4) ◽  
pp. 520-529 ◽  
Author(s):  
Emmanuel Griessinger ◽  
Fernando Anjos-Afonso ◽  
Irene Pizzitola ◽  
Kevin Rouault-Pierre ◽  
Jacques Vargaftig ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Culture System ◽  
Myeloid Leukemia ◽  
Self Renewal ◽  
Human Acute Myeloid Leukemia ◽  
Acute Myeloid

Long-Term Expansion and Self Renewal Is Contained in the CD34+, but Not the CD34- Subfraction of Nucleophosmin Mutated Acute Myeloid Leukemia Cells.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1349-1349
Author(s):  
Carolien Woolthuis ◽  
Lina Han ◽  
Djoke van Gosliga ◽  
Philip Kluin ◽  
Edo Vellenga ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hox Genes ◽  
Mutant Protein ◽  
Self Renewal ◽  
Cd34 Cells ◽  
Stromal Layer ◽  
Acute Myeloid

Abstract Mutations in the nucleophosmin (NPM) gene are found in about 30% of cases of acute myeloid leukemia (AML) and lead to a dislocation of the nucleophosmin protein from the nucleus to the cytoplasm (NPMc+ AML). NPMc+ AML shows distinctive biological and clinical features, including a unique gene expression profile, a distinct microRNA signature, low percentage of CD34+ cells, increased incidence of Flt3-ITD (about 40% of cases), good response to induction chemotherapy and (in the absence of Flt3-ITD) a favourable prognosis. Despite significant progress in the characterization of the NPMc+ AML subgroup, questions remain about the leukemia-initiating cell. Distinct features of NPMc+ AML, including multilineage involvement and overexpression of HOX-genes, may point to an early progenitor as the leukemia-initiating cell, but the characteristic low percentage of CD34+ cells may point to a more differentiated leukemic stem cell in NPMc+ AML. To gain more insight in the leukemia-initiating cell in AML with mutated NPM, NPMc+ AML cells were sorted based on the expression of CD34 (n=8, the percentage of CD34+ in the total AML fraction varied between 0.06 and 37%). Western blotting, using an antibody that specifically recognizes the nucleophosmin mutant protein revealed that the NPM mutant protein is expressed in both CD34+ and CD34− cells, proving that the CD34+ NPMc+ AML cells belong to the leukemic clone. This was verified by sequencing the NPM gene in CD34+ and CD34− AML cells. Importantly, culture of sorted CD34+ and CD34− NPMc+ AML cells on a stromal layer revealed that the CD34+ but not the CD34− cells of NPMc+ AML were capable of expanding and initiating long-term growth. In the first 5 weeks of culture an at least 16 fold (range 16–208) expansion of CD34+ AML cells was seen in 5 out of 6 NPMc+ AML cases. This expansion was associated with the formation of cobblestone areas (CAs) under the stromal layer within 3 weeks after plating. The NPMc+ AML cells which expanded in culture were able to expand further after replating in 4 out of 5 investigated cases (fold expansion range 1.6–2.5), indicative of the self renewal capacity of these CD34+ NPMc+ AML cells. Gene expression analysis of CD34+ and CD34− NPMc+ AML cells of 4 cases analyzed thus far revealed the presence of the characteristic HOX-overexpression profile in both CD34+ and CD34− NPMc+ AML cells. In summary, this study shows that the NPM mutation is not only present in CD34−, but also in CD34+ cells of NPMc+ AML and that the properties of long-term expansion and self renewal belong exclusively to the CD34+ subfraction of NPMc+ AML.

Co-Existence of LMPP-Like and GMP-Like Leukemia Stem Cells In Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 91-91
Author(s):  
Nicolas Goardon ◽  
Emmanuele Marchi ◽  
Lynn Quek ◽  
Anna Schuh ◽  
Petter Woll ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Leukemic Stem Cell ◽  
Self Renewal ◽  
Two Populations ◽  
Acute Myeloid

Abstract Abstract 91 In normal and leukemic hemopoiesis, stem cells differentiate through intermediate progenitors into terminal cells. In human Acute Myeloid Leukemia (AML), there is uncertainty about: (i) whether there is more than one leukemic stem cell (LSC) population in any one individual patient; (ii) how homogeneous AML LSCs populations are at a molecular and cellular level and (iii) the relationship between AML LSCs and normal stem/progenitor populations. Answers to these questions will clarify the molecular pathways important in the stepwise transformation of normal HSCs/progenitors. We have studied 82 primary human CD34+ AML samples (spanning a range of FAB subtypes, cytogenetic categories and FLT3 and NPM1 mutation states) and 8 age-matched control marrow samples. In ∼80% of AML cases, two expanded populations with hemopoietic progenitor immunophenotype coexist in most patients. One population is CD34+CD38-CD90-CD45RA+ (CD38-CD45RA+) and the other CD34+CD38+CD110-CD45RA+ (GMP-like). Both populations from 7/8 patients have leukemic stem cell (LSC) activity in primary and secondary xenograft assays with no LSC activity in CD34- compartment. The two CD34+ LSC populations are hierarchically ordered, with CD38-CD45RA+ LSC giving rise to CD38+CD45RA+ LSC in vivo and in vitro. Limit dilution analysis shows that CD38-CD45RA+LSCs are more potent by 8–10 fold. From 18 patients, we isolated both CD38-CD45RA+ and GMP-like LSC populations. Global mRNA expression profiles of FACS-sorted CD38-CD45RA+ and GMP-like populations from the same patient allowed comparison of the two populations within each patient (negating the effect of genetic/epigenetic changes between patients). Using a paired t-test, 748 genes were differentially expressed between CD38-CD45RA+ and GMP-like LSCs and separated the two populations in most patients in 3D PCA. This was confirmed by independent quantitative measures of difference in gene expression using a non-parametric rank product analysis with a false discovery rate of 0.01. Thus, the two AML LSC populations are molecularly distinct. We then compared LSC profiles with those from 4 different adult marrow normal stem/progenitor cells to identify the normal stem/progenitor cell populations which the two AML LSC populations are most similar to at a molecular level. We first obtained a 2626 gene set by ANOVA, that maximally distinguished normal stem and progenitor populations. Next, the expression profiles of 22 CD38-CD45RA+ and 21 GMP-like AML LSC populations were distributed by 3D PCA using this ANOVA gene set. This showed that AML LSCs were most closely related to their normal counterpart progenitor population and not normal HSC. This data was confirmed quantitatively by a classifier analysis and hierarchical clustering. Taken together, the two LSC populations are hierarchically ordered, molecularly distinct and their gene expression profiles do not map most closely to normal HSCs but rather to their counterpart normal progenitor populations. Finally, as global expression profiles of CD38-CD45RA+ AML LSC resemble normal CD38-CD45RA+ cells, we defined the functional potential of these normal cells. This had not been previously determined. Using colony and limiting dilution liquid culture assays, we showed that single normal CD38-CD45RA+ cells have granulocyte and macrophage (GM), lymphoid (T and B cell) but not megakaryocyte-erythroid (MK-E) potential. Furthermore, gene expression studies on 10 cells showed that CD38-CD45RA+ cells express lymphoid and GM but not Mk-E genes. Taken together, normal CD38-CD45RA+ cells are most similar to mouse lymphoid primed multi-potential progenitor cells (LMPP) cells and distinct from the recently identified human Macrophage Lymphoid progenitor (MLP) population. In summary, for the first time, we show the co-existence of LMPP-like and GMP-like LSCs in CD34+ AML. Thus, CD34+ AML is a progenitor disease where LSCs have acquired abnormal self-renewal potential (Figure 1). Going forward, this work provides a platform for determining pathological LSCs self-renewal and tracking LSCs post treatment, both of which will impact on leukemia biology and therapy. Disclosures: No relevant conflicts of interest to declare.

ETO2-GLIS2 Controls Differentiation Arrest and Self-Renewal through Aberrant Enhancers Regulation in Pediatric Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 572-572
Author(s):  
Cecile Thirant ◽  
Cecile K Lopez ◽  
Cathy Ignacimouttou ◽  
M'Boyba Diop ◽  
Lou Le Mouël ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Genetic Alterations ◽  
Leukemic Cells ◽  
Hematopoietic Progenitors ◽  
Pediatric Leukemia ◽  
Self Renewal ◽  
Megakaryocytic Differentiation ◽  
Acute Myeloid

Abstract Deregulated gene expression due to genetic alterations, such as gene fusions affecting transcription and/or epigenetic factors is the hallmark of acute myeloid leukemia and the basis for the differentiation block of hematopoietic progenitors. Acute megakaryoblastic leukemia (AMKL) is a subtype of poor prognosis acute myeloid leukemia (AML) affecting primarily young children. Recently, the ETO2-GLIS2 fusion has been identified in 20-30% of de novo AMKL and associated with the worst prognosis in this subtype of AML. To characterize the transformation induced by ETO2-GLIS2, we first defined the consequences of ETO2-GLIS2 expression on hematopoietic progenitors and the contribution of ETO2 and GLIS2 on differentiation and self-renewal. Using methylcellulose replating assays and phenotype characterization, we show that the GLIS2 moiety drives the megakaryocytic phenotype whereas both the ETO2 and GLIS2 moieties are required for maintaining self-renewal. Global expression profiling and comparison to patients' signature consistently identify ETO2-GLIS2-mediated deregulation of major transcriptional regulators of hematopoiesis and leukemogenesis, including overexpression of the ERG oncogene. ChIP-seq analysis reveals that ETO2-GLIS2 is recruited at normal ETO2 complexes sites and also at GLIS2-specific targets through binding via GLIS2 DNA-binding domain. We demonstrate that ETO2-GLIS2 fusion localize at half of H3K27Ac-dense enhancers, so called super-enhancers, to control transcription of associated genes. We show that interaction of ETO2-GLIS2 with ETO2 complexes is an essential node for the transcriptional control by the fusion at enhancer elements. Indeed, ETO2-GLIS2 dimerizes and interacts with endogenous ETO2 via its NHR2 domains. An NHR2 peptide-interference strategy inhibits oligomerization, reverses the transcriptional activation at enhancers, promotes megakaryocytic differentiation and abrogates human AMKL cells maintenance in vivo. Finally, upregulation of ERG by ETO2-GLIS2 further strengthen enhancers formation as ERG is co-recruited generating a feed forward loop at these elements and its knockdown or genetic inactivation downregulates expression of ETO2-GLIS2 targets required for leukemic cells survival. We propose that the megakaryocytic differentiation arrest and self-renewal controlled by ETO2-GLIS2 results from an imbalance in the expression of master transcription factors imposed by aberrant chromatin structures at enhancers that may be disrupted by targeting the NHR2 interface. Disclosures No relevant conflicts of interest to declare.

scholarly journals Clonal Architecture of Relapsed MLL-AF9 Acute Myeloid Leukemia in a Child

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1014-1014
Author(s):  
Hélène Boutroux ◽  
Pierre Hirsch ◽  
Chrystele Bilhou-Nabera ◽  
Ruoping Tang ◽  
Fanny Fava ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clonal Evolution ◽  
Monocyte Count ◽  
Trisomy 8 ◽  
Self Renewal ◽  
Clonal Architecture ◽  
Leukemic Clone ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Introduction Acute myeloid leukemia (AML) is an aggressive malignancy caused by the accumulation of multiple oncogenetic mutations occurring in a single lineage of hematopoietic progenitors. AML is rare in children and the mutations found are partially different from those in adults, and for some with a lower frequency. Thus, clonal evolution leading to pediatric AML may be specific, and has not been described yet. Methods To define clonal evolution from diagnosis to relapse, we performed whole exome sequencing in matched trio of specimens (diagnosis, germline and relapse) in a 9-years old girl presenting AML FAB M5a with t(9;11)(p22;q23) MLL-AF9 and trisomy 8. At diagnosis, we focused on 3 non-silent somatic mutations candidate for leukemogenesis process, confirmed by Sanger method: EED (R355*), GSDMC (R40*) and ELK1 (3’ UTR). In the same time, we performed cell cultures from bone marrow mononucleated cells at diagnosis. CD34 and CD38 cells were cultured either in liquid long term culture medium (LTC IC) or methylcellulose medium. Results: A total of 512 colonies were collecte. Our 3 interest mutations and trisomy 8 were tracked by allele-specific PCR, and MLL rearrangement detected by FISH, individually in 267 from the 512 colonies. Exploitable results were found in 164 colonies. Through these results in the different cell populations, we were able to establish the clonal architecture at diagnosis. MLL-AF9 fusion and EED mutation were found together as the first concomitant occurring events in the leukemic clone. Then genotyping of the colonies demonstrated that ELK1 mutation, GSDMC mutation, and trisomy 8 were successively acquired. Additional later mutations such as ASXL1 (frameshift), PTPN11 (E76K), EMP2 (3’UTR) and DGCR14 (P314S) were detected in the relapse sample. Discussion The 3 mutations studied in the colonies may impact the progression of the leukemic clone by dysregulating several cellular pathways and networks. First, EED is an essential non-catalytic subunit of the polycomb repressive complex 2 (PRC2) which mediates gene silencing through catalysis of histone H3K27 methylation. PRC2 is known to be enhanced in solid neoplasms such as prostate cancer. On the contrary, in myeloid malignancies and myelodysplasic syndromes, it has been recently demonstrated that mutations involving PRC2 subunits (EED, SUZ12 and EZH1/2) were hypomorphic. These loss-of-functions mutations were responsible for chromatin relaxation and induced transcription of genes promoting self-renewal such as HOXA9. Nevertheless, recent sh-RNA studies in a murine model of MLL-AF9 leukemia demonstrated that residual PRC2 enzymatic activity after EED mutation is needed to unable leukemia growth. These data are coherent with our finding that EED mutation is an early event in leukemogenesis, in cooperation with MLL-AF9 rearrangement. Secondly, ELK1 is targeted by RAS-MAPK pathway, thus its mutation can confer an increased proliferation potential when acquired by the leukemic clone, after its maturation has been blocked and its self-renewal increased through previous MLL rearrangement and EED mutation. Finally, GSDMC may be implicated in monocyte count regulation, and mutated in other neoplasms such as melanoma. As a consequence, it is likely that its mutation occurs lately in the evolution of the monoblastic leukemic clone of our patient. The latest event in the clonal evolution in our patient at diagnosis is the acquisition of trisomy 8. Conclusion This study highlights the clonal evolution in one pediatric AML, and paves the way for further studies to better understand clonal evolution in children. Elucidating, the succession and the cooperation between driver and secondary mutations, is important for both understanding leukemogenesis and developing innovative therapeutic agents targeting founding anomalies in the leukemic clone at its most precocious stage. Moreover, discovering clonal architecture also unable to find new minimal residual disease markers to assess the therapeutic response and risk stratification. Disclosures No relevant conflicts of interest to declare.

scholarly journals Long Non-Coding RNA LINC00152 Regulates Self-Renewal of Leukemia Stem Cells and Induces Chemo-Resistance in Acute Myeloid Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Chunhong Cui ◽  
Yan Wang ◽  
Wenjie Gong ◽  
Haiju He ◽  
Hao Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Underlying Mechanism ◽  
Therapy Resistance ◽  
Initial Therapy ◽  
Leukemia Stem Cells ◽  
Self Renewal ◽  
Acute Myeloid

Relapse of acute myeloid leukemia (AML) has a very poor prognosis and remains a common cause of treatment failure in patients with this disease. AML relapse is partially driven by the chemoresistant nature of leukemia stem cells (LSCs), which remains poorly understood, and our study aimed at elucidating the underlying mechanism. Accumulating evidences show that long noncoding RNAs (lncRNAs) play a crucial role in AML development. Herein, the lncRNA, LINC00152, was identified to be highly expressed in CD34+ LSCs and found to regulate the self-renewal of LSCs derived from AML patients. Importantly, LINC00152 upregulation was correlated with the expression of 16 genes within a 17-gene LSC biomarker panel, which contributed to the accurate prediction of initial therapy resistance in AML. Knockdown of LINC00152 markedly increased the drug sensitivity of leukemia cells. Furthermore, LINC00152 expression was found to be correlated with poly (ADP-ribose) polymerase 1 (PARP1) expression in AML, whereas LINC00152 knockdown significantly decreased the expression of PARP1. Upregulation of LINC00152 or PARP1 was associated with poor prognosis in AML patients. Collectively, these data highlight the importance and contribution of LINC00152 in the regulation of self-renewal and chemoresistance of LSCs in AML.

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