VEGFR-1 (FLT-1), b1 Integrin and hERG K+ Channel Form a Macromolecular Signaling Complex in Acute Myeloid Leukemia Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2366-2366
Author(s):  
Annarosa Arcangeli ◽  
Serena Pillozzi ◽  
Maria F. Brizzi ◽  
Pietro A. Bernabei ◽  
Benedetta Bartolozzi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Cell Migration ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Leukemia Cells ◽  
Signaling Complex ◽  
Negative Prognostic Factor ◽  
Macromolecular Signaling Complex ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous group of clonal bone marrow (BM) malignancies, presenting a wide spectrum of morphologic, immunophenotypic, cytogenetic, and molecular features. There is general agreement that persistent detection of leukemia cells outside the BM microenvironment, especially when accompanied by infiltration into extramedullary sites, is a clear negative prognostic factor. Infiltration may also reduce leukemia responsiveness to induction chemotherapy. Great attention is thus being played to the molecular mechanisms that regulate acute leukemia cells exit from the BM. A crucial role is thought to be played by the angiogenic factors and angiogenesis-related signals, that operate inside the BM microenvironment.The persistence of circulating leukemia blasts and their engraftment into extramedullary sites are negative prognostic factors, in patients with acute leukemia. Leukemia cell exit from the bone marrow is regulated by angiogenic factors and in particular by the Vascular Endothelial Growth Factor and its receptor 1, FLT-1. We have studied the cross talk between FLT-1, the human eag-related gene 1 (hERG1) K+ channels, integrin receptors, in acute myeloid leukemia (AML) cells. FLT-1, hERG1 and the b1 integrin were found to form a macromolecular signaling complex. The latter mostly recruited the hERG1B isoform of hERG1 channels, and its assembly was necessary for subsequent FLT-1 tyrosine phosphorylation and sustained AML cell migration. What is more, both effects were inhibited when hERG1 channel were specifically blocked. The formation of an FLT-1/hERG1/b1 complex was also observed in primary AML blasts, obtained from a population of human patients. The coexpression of FLT-1 and hERG1 conferred a pro-migratory phenotype to these AML blasts. Such a phenotype was also observed in vivo. Herg1 positive blasts were more efficient in invading the peripheral circulation and the extramedullary sites after engraftment into immunodeficient mice. Moreover, herg1 expression in leukemia patients correlated with a shorter overall survival. Overall, we conclude that hERG1 channels mediate the FLT-1 dependent AML cell migration and that their expression is a negative prognostic factor, in AML.

VEGFR-1 (FLT-1), β1 integrin, and hERG K+ channel for a macromolecular signaling complex in acute myeloid leukemia: role in cell migration and clinical outcome

Blood ◽  
2007 ◽  
Vol 110 (4) ◽  
pp. 1238-1250 ◽  
Author(s):  
Serena Pillozzi ◽  
Maria Felice Brizzi ◽  
Pietro Antonio Bernabei ◽  
Benedetta Bartolozzi ◽  
Roberto Caporale ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Migration ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Migration And Invasion ◽  
Β1 Integrin ◽  
Acute Leukemias ◽  
Signaling Complex ◽  
Macromolecular Signaling Complex ◽  
Acute Myeloid

Abstract Leukemia cell motility and transendothelial migration into extramedullary sites are regulated by angiogenic factors and are considered unfavorable prognostic factors in acute leukemias. We have studied cross talk among (1) the vascular endothelial growth factor receptor-1, FLT-1; (2) the human eag-related gene 1 (hERG1) K+ channels; and (3) integrin receptors in acute myeloid leukemia (AML) cells. FLT-1, hERG1, and the β1 integrin were found to form a macromolecular signaling complex. The latter mostly recruited the hERG1B isoform of hERG1 channels, and its assembly was necessary for FLT-1 signaling activation and AML cell migration. Both effects were inhibited when hERG1 channels were specifically blocked. A FLT-1/hERG1/β1 complex was also observed in primary AML blasts, obtained from a population of human patients. The co-expression of FLT-1 and hERG1 conferred a pro-migratory phenotype to AML blasts. Such a phenotype was also observed in vivo. The hERG1-positive blasts were more efficient in invading the peripheral circulation and the extramedullary sites after engraftment into immunodeficient mice. Moreover, hERG1 expression in leukemia patients correlated with a higher probability of relapse and shorter survival periods. We conclude that in AML, hERG1 channels mediate the FLT-1–dependent cell migration and invasion, and hence confer a greater malignancy.

Rac1 Gtpase Promotes Hematopoietic Stem Cell Migration, Self-Renewal and Participates in Leukemia Initiation and Maintenance

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2923-2923
Author(s):  
Shuying Chen ◽  
Qing Rao ◽  
Haiyan Xing ◽  
Jing Yu ◽  
Huan Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Cell Migration ◽  
Myeloid Leukemia ◽  
Leukemia Cells ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Rac1 Gtpase ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a hematological malignancy resulting from the transformation of normal hematopoietic stem cell (HSC). Except for the intrinsic factors, it is acceptable that some extrinsic events from microenvironment could be the important co-factors in the development of leukemia. In addition to the specific component, as an extrinsic factor, interaction between HSC and bone marrow niche regulates HSCs fate. Disruption on the interactions also influences hematopoiesis. It has become evident that Rac members of Rho GTPases family are important molecules regulating HSCs interactions with hematopoietic microenvironment and activation of Rac1 are observed in a serials of leukemia cells. We previously reported that Rac1 is highly expressed in leukemia cells and found that activation of Rac1 GTPase lead to an increase in leukemia cells migration, chemotherapy resistance, quiescence and trafficking to bone marrow niche. Furthermore, we showed that Rac1 mediated the localization in niche is further attributable to the maintenance of LSC quiescence. In this study, we investigated the effects of active Rac1 GTPase in the transformation of HSC and determined if the activation of Rac1GTPase could promote the interaction of HSC with osteoblastic niche and further contribute to the leukomogenesis. By forced expression of a constitutively active form of Rac1 GTPase (Rac1 V12）in c-Kit+ hematopoietic stem/progenitor cell, we show that activation of Rac1 GTPase promotes cell migration, adhesion and colony formation, and also lead to an increase in the frequency of cells in quiescent state. Gene expression analysis shows that activation of Rac1 up-regulates the expression of several molecules that mediated the interaction of LSC with osteoblastic niche, as well as the cell cycle inhibitors such as p21, p27, and p57. Furthermore, we established a mouse model of acute myeloid leukemia by transduction murine c-kit+HSPC with Rac1 V12 combined with AML1-ETO9a, followed by transplantation into lethally irradiated mice. To investigate the role of Rac1 activation in leukemogenesis in vivo, we treated the AML1-ETO-Rac1 leukemia cells with Rac1 GTPase inhibitor EHT1846 and then transplanted into recipient mice. After 40 μM EHT1846 treatment, no engraftment of AML cells in recipient mice was observed. Kaplan-Meier analyses indicate that treatment with EHT1846 significantly prolongs survival of the transplanted mice. 20μM dose of EHT1846 was less effective. These data indicated that active Rac1 might be an important contributing factor to leukemogenesis. In addition, short-term homing assays showed that EHT 1846 treatment causes a marked inhibition of AML cell homing into both bone marrow and spleen as compared with controls, indicating that Rac1 mediated homing could be an important step and participated in the leukemogensis. Altogether, our data suggest that activation of Rac1 GTPase is critical for the interaction between HSCs with BM niche and even be contributed to leukemia development. Disclosures Wang: Novartis: Consultancy; Bristol Myers Squibb: Consultancy.

scholarly journals SETDB1 mediated histone H3 lysine 9 methylation suppresses MLL-fusion target expression and leukemic transformation

Haematologica ◽  
2019 ◽  
Vol 105 (9) ◽  
pp. 2273-2285 ◽  
Author(s):  
James Ropa ◽  
Nirmalya Saha ◽  
Hsiangyu Hu ◽  
Luke F. Peterson ◽  
Moshe Talpaz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Critical Role ◽  
High Expression ◽  
Leukemia Cells ◽  
Biological Impact ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Epigenetic regulators play a critical role in normal and malignant hematopoiesis. Deregulation, including epigenetic deregulation, of the HOXA gene cluster drives transformation of about 50% of acute myeloid leukemia. We recently showed that the Histone 3 Lysine 9 methyltransferase SETDB1 negatively regulates the expression of the pro-leukemic genes Hoxa9 and its cofactor Meis1 through deposition of promoter H3K9 trimethylation in MLL-AF9 leukemia cells. Here, we investigated the biological impact of altered SETDB1 expression and changes in H3K9 methylation on acute myeloid leukemia. We demonstrate that SETDB1 expression is correlated to disease status and overall survival in acute myeloid leukemia patients. We recapitulated these findings in mice, where high expression of SETDB1 delayed MLL-AF9 mediated disease progression by promoting differentiation of leukemia cells. We also explored the biological impact of treating normal and malignant hematopoietic cells with an H3K9 methyltransferase inhibitor, UNC0638. While myeloid leukemia cells demonstrate cytotoxicity to UNC0638 treatment, normal bone marrow cells exhibit an expansion of cKit+ hematopoietic stem and progenitor cells. Consistent with these data, we show that bone marrow treated with UNC0638 is more amenable to transformation by MLL-AF9. Next generation sequencing of leukemia cells shows that high expression of SETDB1 induces repressive changes to the promoter epigenome and downregulation of genes linked with acute myeloid leukemia, including Dock1 and the MLL-AF9 target genes Hoxa9, Six1, and others. These data reveal novel targets of SETDB1 in leukemia that point to a role for SETDB1 in negatively regulating pro-leukemic target genes and suppressing acute myeloid leukemia.

A Novel Non-Genetic Photostable Approach to Labelling Acute Myeloid Leukemia and Bone Marrow Cells with Quantum Dots

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4818-4818
Author(s):  
Yanwen Zheng ◽  
Zhengwei Mao ◽  
Bin Yin
Keyword(s):  
Bone Marrow ◽  
Quantum Dots ◽  
Acute Myeloid Leukemia ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
Hematopoietic Cells ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Dependent Manner ◽  
Acute Myeloid

Abstract Abstract 4818 Acute myeloid leukemia (AML) is a detrimental disease with difficult diagnosis and treatment. Understanding the biology of AML at the molecular and cellular levels would be essential to successful management of the disease. However, the notoriously known difficulty in manipulation of leukemia cells has long hindered the dissection of AML pathogenesis. The advent of CdSe/ZnS quantum dots (QDs) represents an important advancement in the research field of nanotechnology, which have recently also been applied for imaging of live cells. Here, we have introduced a non-genetic approach of marking blood cells, by taking advantage of QD technology. We compared QDs complexed with different vehicles, including a peptide Tat (QDs-Tat), cationic polymer Turbofect (QDs-Tf) and liposome Lipofectamine 2000 (QDs-Lip), in their abilities to mark cells. QDs-Tat showed the highest efficiency in delivery into hematopoietic cells, among the three vehicles. We then examined QDs-Tat labelling of leukemia cell lines, and found that QDs-Tat could label 293T, bone marrow (BM) cells, THP-1, MEG-01 and HL-60 with a decreasing efficiency. The efficiency of QDs-Tat delivery was dependent on the concentration of QDs-Tat applied, but not the length of incubation time. In addition, more uniform intracellular distributions of QDs in 293T and leukemia cells were obtained with QDs-Tat, compared with the granule-like formation obtained with QDs-Lip. Clearly, QD fluorescence was sharp and tolerant to repetitive photo excitations, and could be detected in 293T for up to one week following labelling. In summary, our results suggest that QDs have provided a photostable, non-genetic and transient approach that labels normal and malignant hematopoietic cells in a cell type-, vehicle-, and QD concentration-dependent manner. We expect for potentially wide applications of QDs as an easy and fast tool assisting investigations of various types of blood cells in the near future. Disclosures: No relevant conflicts of interest to declare.

The Role of TWIST1 Gene Expression and Hypoxic Microenvironment in Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3839-3839
Author(s):  
Emilia Carolina Malafaia ◽  
A. Mario Marcondes ◽  
Ekapun Karoopongse ◽  
Daniele Serehi ◽  
Maria de Lourdes L. F. Chauffaille ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemia Cells ◽  
Twist1 Expression ◽  
Disease Biology ◽  
Acute Myeloid

Abstract TWIST1, a basic helix-loop-helix (bHLH) transcription factor, plays a critical role in mesodermal development and organogenesis. Overexpressed TWIST1 has been thoroughly related to epithelial-mesenchymal transition (EMT) in solid tumors (QIN Q et al., 2012) and has been described as an emerging risk factor in hematological neoplasms (MERINDOL et al., 2014). . Many questions remain to be addressed concerning to the role of TWIST1 in acute myeloid leukemia (AML). The understanding of TWIST1 in leukemia cells and its interaction with microenvironment can offer new insights in regards to disease biology and therapeutic targets for patients with AML. Objectives: 1) to evaluate the role of stroma contact and hypoxia in TWIST1 expression in myeloid cell lines. 2) To evaluate the functional impact of overexpressing TWIST1 on KG1a and PL21 cells. 3) To evaluate TWIST1 expression in primary cells of AML patients. Methods: In order to mimic bone marrow microenvironment, myeloid cells were co-cultured with mesenchymal HS5 cell line and PO2 1% was established with Smart -Trak¨ 2 (Sierra Instruments, Inc.) equipment. Quantitative mRNA was determined using TaqMan¨ Universal Master Mix (Applied Biosystems, Foster City, CA) and 3-step standard cycling conditions with sequence-specific primer TWIST1 normalized to the expression of β-actin. KG1a and PL21 cells were transduced with lentivirus vector carrying e-GFP ("enhanced green fluorescence protein") for stable expression of TWIST1. Transduced cells were sorted by FITC fluorochrome and then verified through western blot analysis with TWIST1 antibody. For quantification of apoptosis, cells were labeled with PE-conjugated antibody using annexin V-phycoerythrin and propidium iodide (BD Biosciences, USA). DAPI (4',6- diamidino-2-phenylindole dihydrochloride) was used to stain DNA and determine cell cycle information . Apoptosis and cell cycle were analyzed by FACS -Becton Dickinson Canto II (BD Biosciences). Statistical analysis was assessed with unpaired t test. Results: Hypoxia induced TWIST1 mRNA expression in OCIAML3, PL21, KG1a and ML1 cell lines (fold-increased 46.3, 29.8, 12.9 and 2.3 respectively). Cells expressing endogenous TWIST1 protein (OCIAML3 and ML1) showed resistance to apoptosis in a hypoxic microenvironment (normoxia versus hypoxia: OCI/AML3, 22.6 % vs 11.7% and ML1, 29.8% vs. 7.5%) in contrast, cells not expressing endogenous TWIST1 protein (KG1a and PL21) went to apoptosis in the same conditions. Thus, overexpressing TWIST1 in KG1a and PL21 induced apoptosis protection in hypoxia (KG1a unmodified vs. modified: 17.6 ± 6.3 vs. 2.8 ± 6.3, p=0.04; PL21 unmodified vs. modified: 26.9 ± 10.9 vs. 3.2 ± 0.6, p=0.04) (fig 1). We found increased TWIST1 mRNA levels in bone marrow samples of 23 AML patients (3.88 ± 1.59) compared with 5 healthy controls (0.54 ±0.25) (p= 0.02) (fig 2). Patients in the highest tertile of TWIST1 expression did not show differences in percentage of blasts in bone marrow and complete remission after treatment compared with patients in low and middle tertile. Conclusion: Our data suggest TWIST1 gene expression protects acute myeloid leukemia cells from apoptosis in a hypoxic microenvironment. Moreover, our results showed increased expression of TWIST1 in AML patients. Thus, TWIST1 is a potential gene involved in leukemogenesis and should be further explored to understand disease biology and potential therapeutic targets. Disclosures No relevant conflicts of interest to declare.

Disulfiram, an clinically used anti-alcoholism drug has the potential to target acute myeloid leukemia cells in a copper-dependent manner in vivo

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5040-5040
Author(s):  
Bing Xu ◽  
Rongwei Li ◽  
Huijuan Dong ◽  
Feili Chen ◽  
Yuejian Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Specific Antigen ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Control Group ◽  
Acute Myeloid

Abstract Background Disulfiram(DS), an old drug clinically used for alcoholism, was reported to have antitumor effects, recent studies have found that Copper(Cu) can significantly enhance the DS-induced cell death in vitro in a variety of tumor cells. Our previous studies also demonstrated that disulfiram/copper (DS/Cu) couldtarget human leukemia cell lines(like KG1α,Molt4) through the activation of JNK, in vitro. However, there is few report about the ability of DS/Cu in killing cancer cells in vivo. Aims This study aims to explore the effect of DS/Cu on acute myeloid leukemia cell line KG1αin vivo and clarify the underlining mechanism. Methods 6-8 week old female NOD/SCID mice were sublethally irradiated with 2Gy X-ray the day before transplantation, followed by intravenous injection of KG1α cells (1×107 cells) suspended in 0.2 mL of PBS. 5 weeks after transplantation mice were randomly divided into three treatment groups: vehicle (0.9% saline), a combination of DS and Cu daily for 2 weeks, Ara-C alone twice before killing. Mice were sacrificed after 2 weeks treatment with tissues of spleen, liver, bone marrow being observed using histopathology method to detect the invasion of leukemia. The DS/Cu-induced p-c-jun activation was also examined by western blot using tissues of spleen, liver, bone marrow. Statistical analysis was carried out with one-way ANOVA to assess statistical significance (*p < 0.05). Results 4 weeks after transplantation, mice were dispirited with low appetite, down-bent gait, wrinkled fur, slow move, just like suffered from leukemia. What’s more, immature blasts like morphology similar to KG1α were found in the peripheral blood of the mice(11%±3.41). All the mice were sacrificed after 2 weeks treatment, mice in control group were observed with slightly larger spleen and liver with the morphology of invasion of leukemia such as a granular appearance than the other two groups. Histopathology examination showed that leukemia cells infiltrate liver, spleen and bone marrow, and the immunohistochemistry examination found that the leukemia cells in spleen, liver and bone marrow expressed human specific antigen CD45 with the highest expression level in the control group. Moreover, solid tumor could be observed in the peritoneal cavity of two mice in the control group with expression of human specific antigen CD45detected by immunohistochemistry examination. Western blot in this study showed DS/Cu complex induced phosphorylation of c-Jun expression in the spleen, liver and bone marrow. Conclusion DS/Cu complex could effectively target the acute myeloid leukemia cells in the acute leukemia NOD/SCID mice while inhibiting the invasion of leukemia to some extent, and the activation of JNK might play a functional role in DS/Cu mediated antileukemic effects. Disclosures: No relevant conflicts of interest to declare.

Acute Myeloid Leukemia Cells Acquire Chemo-Resistance By Inducing Osteoblast Differentiation in Mesenchymal Stem Cells through up-Regulation of RUNX2

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2929-2929
Author(s):  
Venkata Lokesh Battula ◽  
Phuong M Le ◽  
Jeffrey Sun ◽  
Teresa McQueen ◽  
Anitha Somanchi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Alkaline Phosphatase ◽  
Acute Myeloid Leukemia ◽  
Transcription Factor ◽  
Cell Surface ◽  
Myeloid Leukemia ◽  
Osteoblast Differentiation ◽  
Leukemia Cells ◽  
Acute Myeloid

Abstract The leukemia bone marrow micro-environment (BME) is comprised of the endosteal and vascular niches, provides vital support for cellular growth and conveys drug resistance to leukemia cells. Several reports suggest that mesenchymal stem/stromal cells (MSCs) present in the bone marrow niche induce cell survival and anti-apoptotic proteins in acute myeloid leukemia (AML) cells and protect them from chemotherapy. The mechanisms underlying BME-mediated chemo-resistance however have not been fully elucidated. Here, we hypothesize that AML cells induce functional changes and prime MSCs to protect leukemia cells from chemotherapy. To test our hypothesis, we have compared age matched (between 40-60 years) bone marrow derived MSCs from AML patients (AML-MSC, n=10) and normal (N-MSC, n=10) individuals and analyzed their proliferation, cell surface phenotype, multi-lineage differentiation and chemo-protection potential. AML-MSCs are phenotypically different, with their polygonal morphology and larger cell size compared to N-MSCs which are elongated and spindle shaped appearance. The average cell doubling time of AML-MSCs is 52±8hrs compared to 34±6hours for N-MSCs during their exponential growth phase (p<0.01). Cell surface phenotyping by flow cytometry revealed that most of the markers known to be expressed on N-MSCs including CD105, CD90, CD73, CD51, CD44, SUSD2, CD106, CD140b, CD140a, CD106 and CD271 were also expressed on AML-MSCs at similar levels. Interestingly, tissue non-specific alkaline phosphatase (TNAP, clone W8B2), a cell surface protein highly expressed in naïve-MSCs and osteoblast progenitors (Battula VL et al., Haematologica, 2009) was 10-14 fold higher in AML- as compared to N-MSCs. Since TNAP is also a osteoblast specific marker, we compared osteoblast differentiation potential of N- vs AML-MSCs. Surprisingly, a dramatic increase in alkaline phosphatase activity (by BCIP/NBT substrate) was observed in AML-MSCs even without induction of osteoblast differentiation. mRNA analysis by qRT-PCR revealed that osteoblast specific genes including osteopontin, TNAP, osteocalcin, and osterix were 5-10 fold up-regulated in AML-MSCs compared to N-MSCs before induction. In N-MSCs, the expression of these markers was induced only under osteoblast differentiation conditions. These data indicate that AML-MSCs are primed to differentiate into-osteoblasts. Adipocyte differentiation was assessed by Oil-Red O staining for lipid droplets and revealed a > 95% reduction (p<0.0001) in the number mature adipocytes in AML-MSCs compared to N-MSCs suggesting that AML-MSCs lack the ability to differentiate into adipocytes. To understand the mechanism inducing osteogenic specific differentiation of AML-MSCs, we performed mRNA expression analysis of genes that regulate this process. We found RUNX2, a transcription factor that induces osteogenic but inhibits adipogenic differentiation, was 4-5 fold increased in AML-MSCs compared to N-MSCs. To validate these observations, we co-cultured N-MSCs in the presence or absence of OCI-AML3 cells for 3-5 days and FACS sorted the MSCs for gene expression analysis. We observed a 3-4 fold up-regulation of TNAP protein expression by flow cytometry and 4-6 fold up-regulation of osteoblast specific markers including osteopontin, alkaline phosphatase and osterix in MSCs co-cultured with OCI-AML3 cells. In addition, RUNX2 was up-regulated in MSCs when co-cultured with OCI-AML3 cells. These data suggest that AML cells induce osteogenic differentiation in BM-MSCs by up-regulation of RUNX2. To identify the clinical significance of these observations, we examined the ability of AML- and N-MSCs to protect AML cells from chemotherapy. Co-culture of OCI-AML3 cells with either AML- or N-MSCs and treatment with Cytarabine revealed a 15±4.5% increase in the number of live leukemia cells when co-cultured with AML-MSCs compared to N-MSCs. These data indicate that AML-MSCs protect leukemia cells better from chemotherapy than normal MSCs. In conclusion, AML cells induce osteogenic differentiation in MSCs through up-regulation of the RUNX2 transcription factor. Increased chemo-protection of AML cells by AML-MSCs suggests a prominent role of these cells in AML relapse. Targeting RUNX2 and thereby inhibition of osteoblast differentiation of MSCs may provide enhanced treatment options for AML therapy. Disclosures No relevant conflicts of interest to declare.

Acute Myeloid Leukemia Cells Acquire Stem Cell Features in the Bone Marrow Microenvironment

2014 ◽  
Vol 14 ◽  
pp. S119-S120
Author(s):  
V. Lokesh Battula ◽  
Juliana Benito ◽  
Anitha G. Somanchi ◽  
Seshagiri Duvvuri ◽  
Lauren Hodgson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Bone Marrow Microenvironment ◽  
Leukemia Cells ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid
Sign in / Sign up

Export Citation Format

Share Document