scholarly journals Acute Myeloid Leukemia-Derived Exosomes Transform Bone Marrow Niche into Leukemic Niche.

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 352-352
Author(s):  
Bijender Kumar ◽  
Mayra Garcia ◽  
Lihong Weng ◽  
Xiaoman Lewis ◽  
Jodi Murakami ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Bone Marrow Niche ◽  
Stromal Compartment ◽  
Bm Niche ◽  
Acute Myeloid

Abstract Increasing evidence suggests that leukemia cells take shelter in the bone marrow (BM) niche, where they hide from chemotherapy and continue to divide. As yet, how leukemia cells alter the BM niche to facilitate their growth and assist them in evading chemotherapy is unclear. In this study, we provide compelling evidences that acute myeloid leukemia (AML), through exosome secretion, transformed the BM niche to facilitate their own growth and suppress normal hematopoiesis. Using AML xenograft and MLL-AF9 knock-in mouse model, we show that leukemia cells as well as AML-derived exosomes stimulate the growth of BM stromal progenitors and blocked the osteolineage development in our stromal compartment analysis. Histological analysis and micro-CT examination confirmed loss or thinning of the bone in both leukemia and leukemic exosome-treated animals. Expression of cell adhesion molecules (NCAM1, VCAM1, CD44, OPN & ICAM1) and factors important for angiogenesis (Angpt1, Angpt2 and VEGF) are upregulated, whereas genes important for HSC maintenance (CXCL12 and SCF), osteoblast (OCN, OSX, Notch3 and IGF1) and chondrocyte (ACAN, SOX9) development are suppressed. While we observed increases in phenotypic LT-HSC in AML-derived exosomes treated mice, these mice show reduced multilineage reconstitution ability, increased cell cycle entry and higher sensitivity to myeloablative stress suggesting that HSCs from exosome-treated mice have lower stem cell activity than their counterparts from normal mice.In addition, leukemia-modified stroma cells exhibit marked reduction in ability to support normal HSCs. Pre-treatment of AML-derived exosome “prime” the animal for leukemia cell invasion and accelerate leukemia progression. Conversely,disruption of exosome secretion by targeting Rab27a in AML cells significantly delays leukemia progression. These data strongly support the notion that leukemia-modified niches favor leukemic cell proliferation and suppress normal hematopoiesis. Disclosures No relevant conflicts of interest to declare.

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.

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.

The Synergistic Effect of DNA Methylation Inhibitor 5-Azacytidine and Bcl-2 Signaling Blockade ABT-737 Combination Treatment Induce Apoptosis In AML

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3311-3311
Author(s):  
Yuexi Shi ◽  
Twee Tsao ◽  
Hongbo Lu ◽  
Sergej Konoplev ◽  
Wendy D. Schober ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Cytotoxic Agents ◽  
Leukemia Cells ◽  
Clinical Activity ◽  
Acute Myeloid

Abstract Abstract 3311 Bcl-2 family proteins are key regulators of apoptosis. Aberrations in Bcl2 levels are known to promote tumorigenesis and chemoresistance. Thus strategies to target Bcl2 will likely provide effective therapies for malignancies such as acute myeloid leukemia (AML). ABT-737 is a small molecule BH3 mimetic that binds tightly to a hydrophobic cleft on Bcl-2 and Bcl-XL and exerts its proapoptotic function by preventing antiapoptotic Bcl-2 family members from sequestering activating BH3 proteins (Oltersdorf et al., Nature 2005). We have reported that ABT-737 effectively kills acute myeloid leukemia blast, progenitor, and stem cells without affecting normal hematopoietic cells. ABT-737 induces the disruption of the BCL-2/BAX complex and BAK-dependent but BIM-independent activation of the intrinsic apoptotic pathway (Konopleva et al., Cancer Cell 2006). The ABT-737 related clinical compound, ABT-263, is undergoing Phase I/II studies in chronic lymphocytic leukemia, with initial signs of clinical activity. However, the main side effect is thrombocytopenia resulting from inhibition of Bcl-XL. Hence, combinations of ABT-737 with non-cytotoxic agents are desirable to take full advantage of ABT236's unique spectrum of biophysical and preclinical activities. In this project, we studied pharmacologic interactions between ABT-737 and the DNA methyltransferase inhibitor 5-azacytidine (5-azaC). 5-azaC is a cytidine analog with clinical activity in myelodysplastic syndromes (MDS) and in AML. Since recent studies indicate that 5-azaC induce DNA damage in p53-dependent fashion, we tested the hypothesis that the pro-apoptotic effects of 5-azaC/ABT-737 combination are related to non-redundant activation of BH3-only proteins and mitochondrial apoptosis in AML cells with wt p53. In vitro, 5-azaC and ABT-737 in combination for 72 hrs induced growth inhibition and apoptosis in AML cell lines OCI-AML3, MOLM-13 and U937 in a highly synergistic, dose-dependent fashion, with combination indices (CIs) ranging from 0.1 to 0.22. These effects were observed even at low concentrations (5-azaC 100nM and ABT-737 10nM, at 10:1 ratio). In contrast, no synergistic apoptosis was seen in p53-null HL-60 cells. Likewise, ABT-737/5-azaC induced apoptosis in a synergistic fashion in OCI-AML3 cells infected with vector control shRNA (CI=0.04) but failed to induce cell death in OCI-AML3 p53 shRNA cells, indicating critical p53-dependent mechanisms of cell death. In primary AML samples sensitive to ABT-737 alone (n=3), synergistic and additive effects were seen. The combined effects of 5-azaC and ABT-737 were further investigated in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice injected with cells from a patient with primary refractory AML. Seven days after leukemia transplantation, mice were treated with vehicle, ABT-737 (intraperitoneally (IP), 75mg/kg/day for 10 days), 5-azacytidine (IP, 4mg/kg/day for 5 days) or with the combination. Engraftment of patient leukemia cells was analyzed by the immunohistochemical detection of CD45-positive cells in bone marrow and spleen seven weeks after transplantation. Both, ABT-737 and 5azaC each exerted anti-leukemic effects, as evidenced by significant reduction in leukemia cells in bone marrow and spleen (10% and 3% CD45+ cells detectable in 1/3 mice in ABT-737 and 5-azaC groups, respectively), no CD45+ AML cells were detected in organs of 3/3 mice treated with the combination. No overt hemorrhage was detected in the animals. In summary, the combination of 5-azaC and ABT-737 induces synergistic cells death in AML cell lines and in a subset of primary AML samples in a p53-dependent fashion. The mechanisms of this pharmacologic interactions including the p53-dependent upregulation of BH3-only proteins, described by us for ABT-737/MDM2 inhibitor combinations, are currently under investigation. Results suggest that this therapeutic strategy can be successfully utilized in AML patients with low mutation rate and unimpaired signaling of p53. Disclosures: No relevant conflicts of interest to declare.

High Levels of the Adhesion Molecule CD44 on Leukemic Cells Generate Acute Myeloid Leukemia Relapse After Withdrawal of the Initial Transforming Event

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3154-3154
Author(s):  
Ronan Quere ◽  
Silja Andradottir ◽  
Ann Brun ◽  
Roman Zubarev ◽  
Göran Karlsson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Surface Marker ◽  
Leukemic Cells ◽  
Bone Marrow Niche ◽  
Extrinsic Factors ◽  
Leukemic Relapse ◽  
Acute Myeloid

Abstract Abstract 3154 Multiple genetic hits are detected in patients with acute myeloid leukemia (AML). To investigate this further, we developed a tetracycline inducible mouse model of AML, where the initial transforming event, overexpression of HOXA10, can be eliminated. Continuous overexpression of HOXA10 is required to generate AML in primary recipient mice, but is not essential for maintenance of the leukemia. Transplantation of AML to secondary recipients showed that in established leukemias, ∼80% of the leukemia-initiating cells (LICs) in bone marrow stopped proliferating upon withdrawal of HOXA10 overexpression. However, the population of LICs in primary recipients is heterogeneous since ∼20% of the LICs induce leukemia in secondary recipients despite elimination of HOXA10 induced overexpression (HOXA10OFF). Since the withdrawal of the initial transforming event can be made upon demand, we have been able to ask what co-operating events are essential to maintain growth of leukemic cells as overexpression of HOXA10 is removed. Intrinsic genetic activation of several proto-oncogenes was observed in leukemic cells resistant to inactivation of the initial transformation event. We have identified a frequent increase in the activation of the proto-oncogenes JUN, FOS and EGR1 in relapsed leukemia where overexpression of HOXA10 has been withdrawn (HOXA10OFF versus HOXA10ON conditions). In order to further investigate if another possible mechanism is involved in leukemia, upon withdrawal of the primary oncogenic event, we performed proteomic analysis using mass spectrometry. Interestingly, we observed that upon removal of the primary event, leukemia that continued to grow produced high levels of several proteins involved in cell-cell and cell-matrix interactions. Among these proteins, CD44 is expressed on the cell surface and participates in cell transmigration and is an important target, since this surface glycoprotein mediates cell adhesion, migration and homing of hematopoietic cancer cells. To determine whether an increase in CD44 is a key mechanism by which LICs are resistant, we performed a functional test by FACS sorting leukemic cells generated in primary donors and transplanted 20,000 cells expressing different levels of the CD44 surface marker (CD44low, CD44medium and CD44high) in the tail vein of lethally irradiated secondary recipient mice fed doxycycline or ciproxine. When we monitored mice for occurrence of leukemia, outgrowth of leukemic cells was not dependant on the CD44 protein level on the HOXA10ON (doxycycline) condition. Consistent with this, onset of leukemia was not delayed for mice transplanted with CD44low leukemic cells. When mice were fed with ciproxine to turn off HOXA10 overexpression, all mice injected with CD44high leukemic cells developed leukemia, whereas all mice injected with CD44low leukemic cells remained healthy. In conclusion, we confirmed that withdrawal of the initial HOXA10 oncogene promotes the outgrowth of LICs expressing high levels of CD44. This study suggests that extrinsic niche-dependent factors are also involved in the host-dependent outgrowth of leukemias after withdrawal of HOXA10 overexpression event that initiates the leukemia. Here we demonstrate the highly aggressive nature of LICs expressing high levels of CD44 and conversely, show the impaired outgrowth of LICs expressing low levels of this surface marker. In conclusion, our murine model of inducible HOXA10 expression recapitulates many of the features of human AML and is helpful to analyse the “oncogene addiction” and unravel the basic mechanisms involved in initiation and maintenance of leukemia, and to study whether adhesion molecules expressed on the surface of leukemic cells are important factors for leukemic relapse in the microenvironmental niches of the bone marrow. Our findings support the notion that cell intrinsic genetic events are not the only factors causing leukemic relapse, but suggest that host-dependant extrinsic factors in the bone marrow niche may also play a fundamental role in the mechanism mediating leukemic relapse. Disclosures: No relevant conflicts of interest to declare.

Exosomes Mediate Communication Between the Microenvironment and Leukemic Cells in Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3469-3469
Author(s):  
Peter P. Ruvolo ◽  
Rodrigo Jacamo ◽  
Vivian R Ruvolo ◽  
Jared K Burks ◽  
V Lokesh Battula ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cell Communication ◽  
Confocal Imaging ◽  
Leukemic Cells ◽  
Bone Marrow Niche ◽  
Bm Niche ◽  
Healthy Donors ◽  
Acute Myeloid

Abstract Abstract 3469 It is becoming clear that the microenvironment plays a critical role in tumorigenenesis and drug resistance in cancers including Acute Myeloid Leukemia (AML). Mesenchymal stromal cells (MSC) are a key component of the bone marrow (BM) niche where AML cells reside. Our group and others have reported that MSC are critical mediators of leukemic cell engraftment and survival. Much of the emphasis on studies of the role of MSC in the microenvironment has focused on chemokines and cytokine effects especially those involving the SDF-1/CXCR4 axis. While paracrine mechanisms of MSC regulation of leukemic cells are important, in this report we suggest a novel role for MSC in altering AML cells by exosome-mediated transfer of genetic material. It is only within the last 10 years that microvesicles such as exosomes have been implicated in mammalian cell-to-cell communication. In blood biology, this is perhaps best evidenced in the regulation of antigen presenting cells by exosome containing miRs from T cells (Mittelbrunn et al Nat Commun. 2011; 2:282). At present, the role for exosomes in leukemia biology is unknown. Exosomes are derived from late endosomal processing, are enriched in ceramides, and contain proteins that are critical in membrane trafficking such as the tetraspanin CD63. To determine if MSC could transfer exosomes to AML cells, we introduced GFP-tagged CD63 into MSC. Live confocal imaging of MSC revealed that MSC can indeed secrete exosomes. The secreted exosomes are often observed in clusters, likely due to the high ceramide content of the particles. GFP-CD63 containing exosomes from MSC were purified using the Exoquick kit from System Biosciences (Mountain View, CA) and introduced to OCI-AML3 and THP-1 cells. Confocal imaging revealed exosomal uptake by only few leukemia cells; however, cells that contained the microvesicles appeared to contain clusters of these particles. Co-culture of GFP-CD63+ containing MSC with AML derived OCI-AML3 cells or KG-1 cells for 48 hours resulted in transfer of exosomes to leukemic cells as determined by analytical flow cytometry. Roughly 1.5 % of OCI-AML3 and 0.8 % of KG1 cells were found to have incorporated GFP-CD63. Though exosome transfer from MSC to AML cells appears to occur at low frequency, at least under the conditions employed here, the possibility that even a small number of leukemic cells could be altered by this mechanism could have significant ramifications. Introduction of miRs or other non-coding RNAs could profoundly modify the leukemic cells. If the primary site of residence of leukemic stem cells (LSC) is in the BM niche, then MSC could alter LSC thus creating a heterogeneous population of leukemic cells. The question arises how the BM microenvironment of a healthy individual might differ from that of an AML patient. We conducted miR profiling on MSC from normal healthy donors (N = 15) and AML derived MSC (N = 28). Eighteen miRs showed significant differences in expression between the two groups: AML derived MSC were found to express > 2 fold more miR-450b-5p, mir-382, and miR-539. On the other hand, healthy donor MSC express > 2 fold higher levels of mir-19a, miR-93, and miR-542-5p compared to MSC from AML patients. While it is not known how the exosomes of AML derived MSC differ from those of healthy donors, the difference in miR profiles between the two groups suggests that the miR content of their exosomes could vary and that exosomes from each group could have different effects. Determination of the miR content in the exosomes from each group will shed light on possible mechanisms and analysis is underway. Finally, it is also possible that MSC could use exosomes to alter the microenvironment itself. Preliminary data obtained by confocal microscopy revealed transfer of CD63+ exosomes from GFP-CD63+ MSC to MSC expressing red fluorescent protein (RFP) during co-culture conditions. At this point, the mechanism of transfer is not clear as it is possible that transfer occurs via cell-to cell contact between MSCs and/or incorporation of secreted exosomes by recipient MSC. Still, this data suggests that MSC can exchange genetic materials and that this novel mechanism could act as a plausible means of modifying the microenvironment. In conclusion, exosomal transfer represents a new mechanism in cell-to-cell communication and is active in the leukemia microenvironment with transfer from normal MSC to AML cells or other component cells of the leukemic bone marrow niche. Disclosures: No relevant conflicts of interest to declare.

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

2016 ◽  
Vol 13 (2) ◽  
pp. 248-259 ◽  
Author(s):  
Hong-Sheng Zhou ◽  
Hong-Sheng Zhou ◽  
Bing Z. Carter ◽  
Michael Andreeff ◽  
Bing Z. Carter ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemia Stem Cells ◽  
Bone Marrow Niche ◽  
Yin And Yang ◽  
Acute Myeloid

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.

Sign in / Sign up

Export Citation Format

Share Document