Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity

2004 ◽  
Vol 5 (7) ◽  
pp. 738-743 ◽  
Author(s):  
Kristin J Hope ◽  
Liqing Jin ◽  
John E Dick
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Leukemic Stem Cell ◽  
Self Renewal ◽  
Acute Myeloid

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.

scholarly journals Leukemic Stem Cell Frequency: A Strong Biomarker for Clinical Outcome in Acute Myeloid Leukemia

PLoS ONE ◽  
2014 ◽  
Vol 9 (9) ◽  
pp. e107587 ◽  
Author(s):  
Monique Terwijn ◽  
Wendelien Zeijlemaker ◽  
Angèle Kelder ◽  
Arjo P. Rutten ◽  
Alexander N. Snel ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Leukemic Stem Cell ◽  
Cell Frequency ◽  
Acute Myeloid

scholarly journals Molecular Mutations and Their Cooccurrences in Cytogenetically Normal Acute Myeloid Leukemia

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Mengning Wang ◽  
Chuanwei Yang ◽  
Le Zhang ◽  
Dale G. Schaar
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Clinical Outcomes ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Treatment Decision ◽  
Driver Mutations ◽  
Stem Cell Population ◽  
Leukemic Stem Cell ◽  
Acute Myeloid

Adult acute myeloid leukemia (AML) clinically is a disparate disease that requires intensive treatments ranging from chemotherapy alone to allogeneic hematopoietic cell transplantation (allo-HCT). Historically, cytogenetic analysis has been a useful prognostic tool to classify patients into favorable, intermediate, and unfavorable prognostic risk groups. However, the intermediate-risk group, consisting predominantly of cytogenetically normal AML (CN-AML), itself exhibits diverse clinical outcomes and requires further characterization to allow for more optimal treatment decision-making. The recent advances in clinical genomics have led to the recategorization of CN-AML into favorable or unfavorable subgroups. The relapsing nature of AML is thought to be due to clonal heterogeneity that includes founder or driver mutations present in the leukemic stem cell population. In this article, we summarize the clinical outcomes of relevant molecular mutations and their cooccurrences in CN-AML, includingNPM1,FLT3ITD,DNMT3A,NRAS,TET2,RUNX1,MLLPTD,ASXL1,BCOR,PHF6,CEBPAbiallelic,IDH1,IDH2R140, andIDH2R170, with an emphasis on their relevance to the leukemic stem cell compartment. We have reviewed the available literature and TCGA AML databases (2013) to highlight the potential role of stem cell regulating factor mutations on outcome within newly defined AML molecular subgroups.

Detection, Phenotype and Prognostic Significance of the Leukemic Stem Cell Side PopulationHo342low in Acute Myeloid Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2586-2586
Author(s):  
Juana Serrano-Lopez ◽  
Josefina Serrano ◽  
Joaquín Sanchez-Garcia ◽  
Noemi Fernandez-Escalada ◽  
Maria del Carmen Martinez-Losada ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Common Finding ◽  
Prognostic Impact ◽  
Leukemic Stem Cell ◽  
Conventional Chemotherapy ◽  
Healthy Donors ◽  
Acute Myeloid

Abstract Abstract 2586 Introduction: Acute Myeloid Leukemia (AML) is a heterogeneous disorder arising from a clonal expansion of Leukemic Stem Cell (LSC). The characterization of LSC is crucial because it is resistant to conventional chemotherapy and is ultimately responsible for leukemic relapses. The LSC in AML is a phenotypically heterogeneous population (CD34+CD38-, CLL1 +, CD96 +…). In this sense, “Side Population” cells (SPHo342Low) are considered to be a type of stem cells that can self-renew and differentiate into tissues. SP are characterized by their ability to efflux the vital dye Hoechst 33342 through the drug ABCG2 pump. SPHo342Low cells have been described in many types of solid tumors and AML as potential LSC. The objective in this study is to analyze the frequency of SPHo342Low in AML, their phenotype and the possible prognostic impact on outcomes. Patients and Methods: Bone marrow samples (BM) obtained from 57 patients (median age 58 years, range: 4–82), diagnosed with AML between Mar-07 to Mar-12, were included. Distribution of cytogenetic risk groups was: Favorable (12.5%), Intermediate (60.7%) and Unfavorable (26.8%). NPM1mut was present in 11 cases and FLT3-ITD in 6 cases. Prior MDS was present in 10 cases. After achieving complete remission (CR) with conventional chemotherapy, allogeneic or autologous stem cell transplantation was performed in 17 and 12 patients respectively, according to individual risk and availability of donor. Eleven frail patients received as front-line, low intensity therapy with Azacytidine. We detected LSC, SPHo342Low in marrow MNCs obtained at diagnosis (N=40), at morphologic complete remission (CR) (N=21) or at relapsed / resistant (N=16) disease. For detection, 2×10(6) MNC/ml were resuspended in HBSS medium with 5 ug/ml of Ho342 dye and CD45-FITC, CD34-PE Mn-Abs, analyzing at least 1×105 viable cells in UV laser FACSVantage cytometer with the combination of filters BP 670/40 for emission in red and BP 450/30 for the blue emission. We verified SP region by inhibiting ABCG2 pump with Verapamil (50μM/mL). As controls we analyzed MNCs from BM aspirates from healthy donors (N=5). Results: In all BM samples from healthy donors, SPHo342Low population was detected accounting for 0.5% (range: 0.1 to 0.9%) and it was CD34negCD45neg phenotype in 80% of cases. SPHo342Low cells were detected in 23/40 cases (57.5%) of samples from AML diagnosis with a median of 0.08% (range 0.01–2.3%). Phenotype of SPHo342Low cells at diagnosis was CD34+CD45+/− in 36% of cases. The presence of SPHo342Low cells presented in AML at diagnosis did not statistically correlate with any prognostic clinical variables such as age, cytogenetic-molecular risk or prior MDS. Interestingly, the detection of LSC SPHo342Low at diagnosis was statistically associated to the presence of >0.1% of CD34+CD38- AML cells (P=0,03). In BM samples obtained from AML patients in CR, SPHo342Low cells were detected in 17/21 (81.0%) with a median of 0.17% (range: 0.1 to 0.76%), with a phenotype mostly CD34 negative. In BM samples obtained from AML patients in relapsed/refractory situation, SPHo342Low cells were detected in 14/16 (87.5%) with a median of 0.22% (range: 0.2 to 0.91%) with a phenotype of CD34+ CD45+/− in 33% of cases. Interestingly, patients who did not achieve CR, have a significantly higher percentage of SPHo342Low at diagnosis (0.42% vs. 0.06%, P = 0.044) as well as those who need more than one cycle to achieve CR (0.52% vs. 0.07%, P = 0.04). Moreover, for those patients achieving CR, persistence of Minimal Residual Disease (MRD+) was associated to a higher percentage of SPHo342Low at diagnosis (0.28% vs. 0.05%, P = 0.021). Likewise, Relapse-free survival (RFS) was significantly higher in AML patients lacking SPHo342Low at diagnosis (70 ± 18.2% vs. 43.3 ± 17.6%, P = 0.0324, Log rank test). Conclusions: Detection of LSC SPHo342Low+CD34+CD45+/− phenotype in AML at diagnosis is a common finding that is associated with increased resistance to achieve CR, clearance of MRD and lower RFS. During progression of disease this SPHo342Low+ population increases and maintains CD34+CD45neg phenotype. BM samples obtained from AML patients at CR were SPHo342Low+ CD34negCD45+/− phenotype which can be considered responsible for normal hematopoietic regeneration. Disclosures: No relevant conflicts of interest to declare.

439 Dual modes of action for anti-TIM-3 antibody MBG453 in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML): preclinical evidence for immune-mediated and anti-leukemic activity

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A465-A465
Author(s):  
Catherine Sabatos-Peyton ◽  
Tyler Longmire ◽  
Lisa Baker ◽  
Nidhi Patel ◽  
Anne-Sophie Wavreille ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Leukemic Stem Cells ◽  
Self Renewal ◽  
Immune Mediated ◽  
Acute Myeloid ◽  
Cell Stem Cell

BackgroundTIM-3 is expressed on leukemic stem cells (LSCs) and blasts in AML,1 2 and TIM-3 expression on MDS blasts correlates with disease progression.3 Functional evidence for TIM-3 in AML was established with an anti-TIM-3 antibody which inhibited engraftment and development of human AML in immuno-deficient murine hosts.1 TIM-3 promotes an autocrine stimulatory loop via the TIM-3/Galectin-9 interaction, supporting LSC self-renewal.4 In addition to its cell-autonomous role on LSCs/blasts, TIM-3 also has a critical role in immune system regulation, in adaptive (CD4+ and CD8+ T effector cells, regulatory T cells) and innate (macrophages, dendritic cells, NK cells) immune responses.5 MBG453 is a high-affinity, humanized anti-TIM-3 IgG4 antibody (Ab) (stabilized hinge, S228P), which blocks the binding of TIM-3 to phosphatidylserine (PtdSer). Recent results from a multi-center, open label phase Ib dose-escalation study (NCT03066648) in patients with high-risk MDS and no prior hypomethylating agent therapy evaluating MBG453 in combination with decitabine demonstrated encouraging preliminary efficacy with an overall response rate of 58%,6 and MBG453 combined with azacitidine also showed encouraging response rates.7 Preclinical experiments were undertaken to define the mechanism of action of the hypomethylating agent and anti-TIM-3 combination.MethodsTHP-1 cells (a human monocytic AML cell line) were pre-treated with decitabine and co-cultured with anti-CD3 activated healthy human donor peripheral blood mononuclear cells (PBMCs) in an Incucyte-based assay to measure cell killing. The ability of MBG453 to mediate antibody-dependent cellular phagocytosis (ADCP) was measured by determining the phagocytic uptake of an engineered TIM-3-overexpressing Raji cell line in the presence of MBG453 by phorbol 12-myristate 13-acetate (PMA)-activated THP-1 cells. Patient-derived AML xenograft studies were undertaken in immune-deficient murine hosts to evaluate the combination of decitabine and MBG453.ResultsMBG453 was determined to partially block the TIM-3/Galectin-9 interaction in a plate-based MSD (Meso Scale Discovery) assay, supported by a crystal structure of human TIM-3.8 Pre-treatment of THP-1 cells with decitabine enhanced sensitivity to immune-mediated killing in the presence of MBG453. MBG453 was determined to mediate modest ADCP, relative to controls. MBG453 did not enhance the anti-leukemic activity of decitabine in patient-derived xenograft studies in immuno-deficient hosts.ConclusionsTaken together, these results support both direct anti-leukemic effects and immune-mediated modulation by MBG453. Further studies are ongoing to determine: (1) whether MBG453 can mediate physiologically relevant ADCP of TIM-3-expressing leukemic cells; and (2) the potential of MBG453 to impact the autocrine feedback loop of TIM-3/Galectin-9.Ethics ApprovalThe human tissue used in these studies was under the Novartis Institutes of BioMedical Research Ethics Board IRB, Approval Number 201252867.ReferencesKikushige Y, Shima T, Takayanagi S, et al. TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells. Cell Stem Cell 2010;7(6):708–717.Jan M, Chao MP, Cha AC, et al. Prospective separation of normal and leukemic stem cells based on differential expression of TIM3, a human acute myeloid leukemia stem cell marker. Proc Natl Acad Sci USA 2011; 108(12): 5009–5014.Asayama T, Tamura H, Ishibashi M, et al. Functional expression of Tim-3 on blasts and clinical impact of its ligand galectin-9 in myelodysplastic syndromes. Oncotarget 2017;8(51): 88904–88917.Kikushige Y, Miyamoto T, Yuda J, et al. A TIM-3/Gal-9 autocrine stimulatory loop drives self-renewal of human myeloid leukemia stem cells and leukemic progression. Cell Stem Cell 2015; 17(3):341–352.Acharya N, Sabatos-Peyton C, Anderson AC. Tim-3 finds its place in the cancer immunotherapy landscape. J Immunother Cancer 2020; 8(1):e000911.Borate U, Esteve J, Porkka K, et al. Phase Ib Study of the Anti-TIM-3 Antibody MBG453 in combination with decitabine in patients with high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Blood 2019;134 (Supplement_1):570.Borate U, Esteve J, Porkka K, et al. Abstract S185: Anti-TIM-3 antibody MBG453 in combination with hypomethylating agents (HMAs) in patients (pts) with high-risk myelodysplastic syndrome (HR-MDS) and acute myeloid leukemia (AML): a Phase 1 study. EHA 2020.Sabatos-Peyton C. MBG453: A high affinity, ligand-blocking anti-TIM-3 monoclonal Ab. AACR 2016.

scholarly journals MLL-AF9– and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C

2016 ◽  
Vol 126 (3) ◽  
pp. 997-1011 ◽  
Author(s):  
Nan Zhu ◽  
Mo Chen ◽  
Rowena Eng ◽  
Joshua DeJong ◽  
Amit U. Sinha ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Self Renewal ◽  
Leukemia Stem Cell ◽  
Acute Myeloid

scholarly journals Mechanisms of Resistence of New Target Drugs in Acute Myeloid Leukemia

2020 ◽  
Author(s):  
Debora Capelli ◽  
Francesco Saraceni ◽  
Diego Menotti ◽  
Alessandro Fiorentini ◽  
Attilio Olivieri
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Elderly Patients ◽  
Myeloid Leukemia ◽  
New Drugs ◽  
Tumor Escape ◽  
Leukemic Stem Cell ◽  
Secondary Aml ◽  
High Incidence ◽  
Acute Myeloid

New drugs targeting single mutations have been recently approved for Acute Myeloid Leukemia (AML) treatment, but allogeneic transplant still remains the only curative option in intermediate and unfavorable risk settings, because of the high incidence of relapse. Molecular analysis repertoire permits the identification of the target mutations and drives the choice of target drugs, but the etherogeneity of the disease reduces the curative potential of these agents. Primary and secondary AML resistance to new target agents is actually an intriguing issue and some of these mechanisms have already been explored and identified. Changes in mutations, release of microenvironment factors competing for the same therapeutic target or promoting the survival of blasts or of the leukemic stem cell, the upregulation of the target-downstream pathways and of proteins inhibiting the apoptosis, the inhibition of the cytochrome drug metabolism by other concomitant treatments are some of the recognized patterns of tumor escape. The knowledge of these topics might implement the model of the ‘AML umbrella trial’ study through the combinations or sequences of new target drugs, preemptively targeting known mechanisms of resistance, with the aim to improve the potential curative rates, expecially in elderly patients not eligible to transplant.

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