Bone marrow niche-mediated survival of leukemia stem cells in acute myeloid leukemia: Yin and Yang

Abstract Leukemia stem cells (LSCs) in acute myeloid leukemia (AML) played important roles in development of leukemia, chemotherapeutic drug resistance, and disease relapse and progression. The identification of LSCs and targeting therapies for them has been under investigation. We examined the CD45 dim CD34 + CD38 - CD133 + cells on bone marrow samples of hematologic malignancies and healthy controls using four-color flow cytometry experiments. Interestingly, the CD45 dim CD34 + CD38 - CD133 + cells were highly expressed in bone marrow of patients with AML compared to that of healthy controls (HC). Moreover, the proportions of CD45 dim CD34 + CD38 - CD133 + cells were also examined in diverse hematology malignancies including AML, CML, DLBCL, MM, MDS, HL, ALL and CLL. These cells were prominently detected in BMCs of AML and CML, but rarely in DLBCL, MM, MDS, ALL, CLL and HL. Additionally, the high levels of the CD45 dim CD34 + CD38 - CD133 + cells in AML patients were an independently significant poor risk factor for overall survival and event free survivals. Therefore, our results suggest that CD45 dim CD34 + CD38 - CD133 + cells in AML might have the potential of leukemia stem cells. In addition, this cell population might be a novel therapeutic target for AML.

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Exploiting epigenetically mediated changes: Acute myeloid leukemia, leukemia stem cells and the bone marrow microenvironment

Advances in Cancer Research - Cancer Stem Cells ◽

10.1016/bs.acr.2018.12.005 ◽

2019 ◽

pp. 213-253 ◽

Cited By ~ 3

Author(s):

Aksinija A. Kogan ◽

Rena G. Lapidus ◽

Maria R. Baer ◽

Feyruz V. Rassool

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Bone Marrow Microenvironment ◽

Leukemia Stem Cells ◽

Acute Myeloid

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CD25 Expression Is Associated with Inferior Clinical Outcomes in Elderly Patients with Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v124.21.3678.3678 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3678-3678 ◽

Cited By ~ 2

Author(s):

Shin-ichiro Fujiwara ◽

Kazuo Muroi ◽

Raine Tatara ◽

Kiyoshi Okazuka ◽

Sato Kazuya ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Elderly Patients ◽

Induction Chemotherapy ◽

Myeloid Leukemia ◽

Leukemia Stem Cells ◽

Cd25 Expression ◽

Blast Cells ◽

Acute Myeloid

Abstract Background: Elderly patients with acute myeloid leukemia (AML) show unfavorable biologic characteristics and inferior clinical outcomes compared to younger patients. Because some elderly patients can benefit from intensive chemotherapy, the identification of prognostic markers is important for therapeutic decision-making. CD25 (interleukin 2 receptor alpha) has been reported to be highly expressed in leukemia stem cells and correlate with adverse outcomes in younger (less than 60 years) patients with AML. However, the significance of CD25 expression in elderly patients with AML has not yet been investigated. Methods: We retrospectively reviewed 154 newly diagnosed AML (de novo, secondary) patients aged 60 years or over (median: 69, range: 60-85 years), admitted between 2005 and 2013 to Jichi Medical University Hospital. Blast cells from bone marrow at diagnosis were identified by flow cytometry (FCM) using CD45/side scatter properties. CD25 expression in the blast region was analyzed by FCM combined with single- and two-color staining. Results: The two-color FCM analysis showed that CD25 was expressed in CD34, CD117, and CD13-positive blast cells. The median CD25 expression of the blast cells was 0.7% (range: 0-75.3%). On the basis of CD25 expression in bone marrow blasts from healthy volunteers (n=5; median, 3.2%; range, 1.5-5.6%), we defined CD25 expression >10% as positivity. In this setting, we identified CD25-positive blasts in 21 patients (14%). CD25+AML was characterized by the MDS/MPN history (30%) and, a low or zero frequency of favorable cytogenetics (0%), FAB M2 subtype (5%), and FAB M3 subtype (0%) compared with CD25-AML (n=133). Among the 118 patients who underwent induction chemotherapy, including 75 patients who received a combination of anthracyclin and cytarabine (Ara-C), 69 (58%) achieved complete remission (CR). CD25+AML was associated with an inferior CR rate (20 vs. 64%, respectively, P=0.003), inferior event-free survival (EFS) (1-year EFS, 0 vs. 33%, respectively, P< 0.001), and inferior overall survival (OS) (2-year OS, 13 vs. 38%, respectively, P=0.003) compared with CD25-AML. On multivariate analysis using the following factors: cytogenetics, age (over 75 years), MDS/MPN history, and intensity of induction chemotherapy, CD25-positivity was a significant risk factor for the CR rate (HR: 8.0, 95% CI: 1.7-36.6; P=0.008) and EFS (HR: 2.3, 95% CI: 1.1-4.7; P=0.021). For CD25+AML, the CR rate was higher with induction chemotherapy using a regimen of low-dose Ara-C combined with granulocyte colony-stimulating factor (50%) than that using a regimen of daunorubicine and Ara-C (0%). However, there was no significant difference in OS between patients with CD25+AML treated with induction chemotherapy and those who treated with best supportive care (2-year OS, 13 vs. 11%, respectively, P=0.29). There were no patients with CD25+AML received stem cell transplantation due to disease progression. Conclusion: This study demonstrated that CD25 is an independent prognostic factor for elderly AML patients. The prognosis of CD25+AML patients is extremely poor; therefore, it is necessary to develop alternative approaches, such as a regime including anti-CD25 antibody, therapy targeting leukemia stem cells, and nonmyeloablative stem cell transplantation. Disclosures No relevant conflicts of interest to declare.

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Faculty Opinions recommendation of Role of altered growth factor receptor-mediated JAK2 signaling in growth and maintenance of human acute myeloid leukemia stem cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718326593.793493199 ◽

2014 ◽

Author(s):

Xiaoyan Jiang ◽

Katharina Rothe

Keyword(s):

Stem Cells ◽

Acute Myeloid Leukemia ◽

Growth Factor ◽

Myeloid Leukemia ◽

Growth Factor Receptor ◽

Leukemia Stem Cells ◽

Human Acute Myeloid Leukemia ◽

Acute Myeloid

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Cell Surface Marker Phenotypes and Gene Expression Profiles of Murine Radiation-Induced Acute Myeloid Leukemia Stem Cells are Similar to Those of Common Myeloid Progenitors

Radiation Research ◽

10.1667/rr2374.1 ◽

2011 ◽

Vol 176 (3) ◽

pp. 311-322 ◽

Cited By ~ 13

Author(s):

Tokuhisa Hirouchi ◽

Miyuki Akabane ◽

Satoshi Tanaka ◽

Ignacia Braga-Tanaka ◽

Akiko Todate ◽

...

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Surface Marker ◽

Leukemia Stem Cells ◽

Radiation Induced ◽

Acute Myeloid

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Patient Heterogeneity in Acute Myeloid Leukemia: Leukemic Cell Communication by Release of Soluble Mediators and Its Effects on Mesenchymal Stem Cells

Diseases ◽

10.3390/diseases9040074 ◽

2021 ◽

Vol 9 (4) ◽

pp. 74

Author(s):

Elise Aasebø ◽

Annette K. Brenner ◽

Maria Hernandez-Valladares ◽

Even Birkeland ◽

Olav Mjaavatten ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Extracellular Matrix ◽

Acute Myeloid Leukemia ◽

Mesenchymal Stem Cells ◽

Conditioned Medium ◽

Untreated Control ◽

Myeloid Leukemia ◽

Control Mscs ◽

Acute Myeloid

Acute myeloid leukemia (AML) is an aggressive bone marrow malignancy, and non-leukemic stromal cells (including mesenchymal stem cells, MSCs) are involved in leukemogenesis and show AML-supporting effects. We investigated how constitutive extracellular mediator release by primary human AML cells alters proteomic profiles of normal bone marrow MSCs. An average of 6814 proteins (range 6493−6918 proteins) were quantified for 41 MSC cultures supplemented with AML-cell conditioned medium, whereas an average of 6715 proteins (range 6703−6722) were quantified for untreated control MSCs. The AML effect on global MSC proteomic profiles varied between patients. Hierarchical clustering analysis identified 10 patients (5/10 secondary AML) showing more extensive AML-effects on the MSC proteome, whereas the other 31 patients clustered together with the untreated control MSCs and showed less extensive AML-induced effects. These two patient subsets differed especially with regard to MSC levels of extracellular matrix and mitochondrial/metabolic regulatory proteins. Less than 10% of MSC proteins were significantly altered by the exposure to AML-conditioned media; 301 proteins could only be quantified after exposure to conditioned medium and 201 additional proteins were significantly altered compared with the levels in control samples (153 increased, 48 decreased). The AML-modulated MSC proteins formed several interacting networks mainly reflecting intracellular organellar structure/trafficking but also extracellular matrix/cytokine signaling, and a single small network reflecting altered DNA replication. Our results suggest that targeting of intracellular trafficking and/or intercellular communication is a possible therapeutic strategy in AML.

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Ex Vivo Assays to Study Self-Renewal and Long-Term Expansion of Genetically Modified Primary Human Acute Myeloid Leukemia Stem Cells

Leukemia - Methods in Molecular Biology™ ◽

10.1007/978-1-59745-418-6_14 ◽

2009 ◽

pp. 287-300 ◽

Cited By ~ 18

Author(s):

Jan Jacob Schuringa ◽

Hein Schepers

Keyword(s):

Stem Cells ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Ex Vivo ◽

Genetically Modified ◽

Leukemia Stem Cells ◽

Self Renewal ◽

Human Acute Myeloid Leukemia ◽

Acute Myeloid

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7-Ketocholesterol Promotes Oxiapoptophagy in Bone Marrow Mesenchymal Stem Cell from Patients with Acute Myeloid Leukemia

Cells ◽

10.3390/cells8050482 ◽

2019 ◽

Vol 8 (5) ◽

pp. 482 ◽

Cited By ~ 5

Author(s):

Jessica Liliane Paz ◽

Debora Levy ◽

Beatriz Araujo Oliveira ◽

Thatiana Correia de Melo ◽

Fabio Alessandro de Freitas ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Cholesterol Oxidation ◽

Specific Cell ◽

Hematopoietic Stem ◽

Shh Pathway ◽

Number Of Cells ◽

Acute Myeloid

7-Ketocholesterol (7-KC) is a cholesterol oxidation product with several biological functions. 7-KC has the capacity to cause cell death depending on the concentration and specific cell type. Mesenchymal stem cells (MSCs) are multipotent cells with the ability to differentiate into various types of cells, such as osteoblasts and adipocytes, among others. MSCs contribute to the development of a suitable niche for hematopoietic stem cells, and are involved in the development of diseases, such as leukemia, to a yet unknown extent. Here, we describe the effect of 7-KC on the death of bone marrow MSCs from patients with acute myeloid leukemia (LMSCs). LMSCs were less susceptible to the death-promoting effect of 7-KC than other cell types. 7-KC exposure triggered the extrinsic pathway of apoptosis with an increase in activated caspase-8 and caspase-3 activity. Mechanisms other than caspase-dependent pathways were involved. 7-KC increased ROS generation by LMSCs, which was related to decreased cell viability. 7-KC also led to disruption of the cytoskeleton of LMSCs, increased the number of cells in S phase, and decreased the number of cells in the G1/S transition. Autophagosome accumulation was also observed. 7-KC downregulated the SHh protein in LMSCs but did not change the expression of SMO. In conclusion, oxiapoptophagy (OXIdative stress + APOPTOsis + autophagy) seems to be activated by 7-KC in LMSCs. More studies are needed to better understand the role of 7-KC in the death of LMSCs and the possible effects on the SHh pathway.

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Gpr44 Mediates the Selenium-Dependent Anti-Leukemic Effect in Acute Myeloid Leukemia

Current Developments in Nutrition ◽

10.1093/cdn/nzaa067_062 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1835-1835

Author(s):

Fenghua Qian ◽

Diwakar Tukaramrao ◽

Jiayan Zhou ◽

Nicole Palmiero ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Murine Model ◽

Myeloid Leukemia ◽

Hematopoietic Stem ◽

Cell Counts ◽

Pparγ Agonist ◽

Acute Myeloid

Abstract Objectives The relapse of acute myeloid leukemia (AML) remains a significant concern due to persistent leukemia stem cells (LSCs) that are not targeted by existing therapies. LSCs show sensitivity to endogenous cyclopentenone prostaglandin J (CyPG) metabolites that are increased by dietary trace element selenium (Se), which is significantly decreased in AML patients. We investigated the anti-leukemic effect of Se supplementation in AML via mechanisms involving the activation of the membrane-bound G-protein coupled receptor 44 (Gpr44) and the intracellular receptor, peroxisome proliferator-activated receptor gamma (PPARγ), by endogenous CyPGs. Methods A murine model of AML generated by transplantation of hematopoietic stem cells (HSCs- WT or Gpr44−/−) expressing human MLL-AF9 fusion oncoprotein, in the following experiments: To investigate the effect of Se supplementation on the outcome of AML, donor mice were maintained on either Se-adequate (Se-A; 0.08–0.1 ppm Se) or Se-supplemented (Se-S; 0.4 ppm Se) diets. Complete cell counts in peripheral blood were analyzed by hemavet. LSCs in bone marrow and spleen were analyzed by flow cytometry. To determine the role of Gpr44 activation in AML, mice were treated with Gpr44 agonists, CyPGs. LSCs in bone marrow and spleen were analyzed. Mice transplanted with Gpr44−/- AML cells were compared with mice transplanted with wild type AML cells and the progression of the disease was followed as above. To determine the role of PPARγ activation in AML, PPARγ agonist (Rosiglitazone, 6 mg/kg, i.p, 14 d) and antagonist (GW9662, 1 mg/kg, i.p. once every other day, 7 injections) were applied to Se-S mice transplanted with Gpr44−/- AML cells and disease progression was followed. Results Se supplementation at supraphysiological levels alleviated the disease via the elimination of LSCs in a murine model of AML. CyPGs induced by Se supplementation mediate the apoptosis in LSCs via the activation of Gpr44 and PPARγ. Conclusions Endogenous CyPGs produced upon supplementation with Se at supraphysiological levels improved the outcome of AML by targeting LSCs to apoptosis via the activation of two receptors, Gpr44 and PPARg. Funding Sources NIH DK 07,7152; CA 175,576; CA 162,665. Office of Dietary Supplements, USDA Hatch funds PEN04605, Accession # 1,010,021 (KSP, RFP).

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