Expression of the regulatory cell cycle proteins p21, p27, p14, p16, p53, mdm2, and cyclin E in bone marrow biopsies with acute myeloid leukemia. Correlation with patients’ survival

2007 ◽  
Vol 203 (4) ◽  
pp. 199-207 ◽  
Author(s):  
Vassiliki Zolota ◽  
Chaido Sirinian ◽  
Maria Melachrinou ◽  
Argyrios Symeonidis ◽  
Dionysios S Bonikos
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cyclin E ◽  
Cell Cycle Proteins ◽  
Bone Marrow Biopsies ◽  
Regulatory Cell ◽  
Acute Myeloid

scholarly journals Immunoistochemical expression of PD-1 and PD-L1 in bone marrow biopsies of patients with acute myeloid leukemia

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Francesco Romano ◽  
Antonino Giulio Giannone ◽  
Sergio Siragusa ◽  
Rossana Porcasi ◽  
Ada Maria Florena
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Immune Escape ◽  
Medical Community ◽  
Immune Checkpoints ◽  
Bone Marrow Biopsies ◽  
Underlying Mechanisms ◽  
Acute Myeloid

tumor immunotherapy is a rapidly evolving field. The discovery of the ability of neoplasms to evade the immune response has shifted the attention of the medical community to the underlying mechanisms of the immune response to tumors, highlighting the importance of so-called immune check points, including CTLA4, TIM-3 and PD-1.  an immune escape mechanism is the activation of the immune checkpoint pathway that contributes to the creation of an immunosuppressive microenvironment and therefore to tumor proliferation.although immune checkpoints have been extensively investigated in solid tumors, the same is not true for hematologic neoplasms, particularly for myeloid malignancies. our study is based on the evaluation of the activation of the PD-1 and PD-L1 pathway in the context of the bone marrow tumor microenvironment of patients with acute myeloid leukemia. To do so we evaluated  34 bone marrow biopsies of patients with acute myeloid leukemia comparing them to 10 controls using immunohistochemical methods.

Expression of Angiopoietins and Their Receptor Tie2 in the Bone Marrow of Patients with Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1894-1894
Author(s):  
Christoph Schliemann ◽  
Ralf Bieker ◽  
Teresa Padro ◽  
Torsten Kessler ◽  
Heike Hintelmann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Critical Role ◽  
Angiogenic Factor ◽  
Term Survival ◽  
Bone Marrow Biopsies ◽  
Cox Regression Analysis ◽  
The Impact ◽  
Acute Myeloid

Abstract Angiopoietin-1 (Ang-1) and its natural antagonist Angiopoietin-2 (Ang-2), both ligands for the receptor tyrosine kinase Tie2, are known to play an essential role in normal and pathological angiogenesis. However, the importance of angiopoietin signaling in the pathophysiology of hematologic neoplasias such as acute myeloid leukemia (AML) remains to be elucidated. We investigated the expression of Ang-1, Ang-2 and Tie2 by immunohistochemical analyses in bone marrow biopsies of 64 adult patients with newly diagnosed AML and correlated angiogenic factor expression with clinicopathological variables and long-term survival. Expression of Ang-2 was significantly increased in the bone marrow of AML patients (median [interquartile ranges]: 4.7 [3.3 – 5.7] AU [arbitrary units]) as compared with 16 control patients (1.5 [1.5 – 1.8] AU; P < 0.0001). In contrast, Ang-1 expression levels in AML patients did not differ from those found in controls. Thus, we observed a reversal of the Ang-1 and Ang-2 expression balance in the neoplastic bone marrow (Ang-2:Ang-1 ratio: 1.73) as compared with normal bone marrow (0.51; P < 0.0001). Furthermore, the angiopoietin receptor Tie2 was significantly overexpressed in leukemic blasts (3.8 [2.8 – 4.9] AU vs. 1.8 [1.6 – 2.3] AU; P < 0.0001). Patients expressing high levels of Ang-2 showed significantly longer overall survival (OS) than those with low Ang-2 levels (52.7 vs. 14.7 months; P = 0.039). The impact of Ang-2 expression on OS was especially evident in AML patients simultaneously expressing low levels of Ang-1 (P = 0.0298). Multivariate Cox regression analysis revealed karyotype and Ang-2 expression as independent prognostic factors for OS (hazard ratio [CI]: 3.06 [1.39 – 6.70] and 0.31 [0.14 – 0.69], respectively; P < 0.01). In conclusion, these data provide evidence that the alteration of angiopoietin balance in favor of Ang-2 may play a critical role in the pathophysiology of AML. Furthermore, high pre-therapeutic bone marrow Ang-2 levels indicate a favorable prognosis in polychemotherapy treated AML by a yet unknown mechanism.

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.

Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia

Blood ◽  
2000 ◽  
Vol 95 (8) ◽  
pp. 2637-2644 ◽  
Author(s):  
Teresa Padró ◽  
Sandra Ruiz ◽  
Ralf Bieker ◽  
Horst Bürger ◽  
Martin Steins ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Induction Chemotherapy ◽  
Microvessel Density ◽  
Myeloid Leukemia ◽  
Remission Induction ◽  
Bone Marrow Biopsies ◽  
Acute Myeloid

The importance of angiogenesis for the progressive growth and viability of solid tumors is well established. In contrast, only few data are available for hematologic neoplasms. To investigate the role of angiogenesis in acute myeloid leukemia (AML), bone marrow biopsies from 62 adults with newly diagnosed, untreated AML (day 0) were evaluated. Further studies were done after the completion of remission induction chemotherapy (day 16 of induction chemotherapy, n = 21; complete remission, n = 20). Microvessels were scored in at least 3 areas (×500 field, 0.126 mm2) of the highest microvessel density in representative sections of each bone marrow specimen using immunohistochemistry for von Willebrand factor and thrombomodulin. Microvessel counts were significantly higher in patients with AML (n = 62) compared with control patients (n = 22): median (interquartile range) 24.0 (21.0-27.8)/×500 field vs 11.2 (10.0-12.0)/×500 field, respectively (P < .001). On day 16 of induction chemotherapy, microvessel density was reduced by 60% (44-66) (P < .001) in hypoplastic marrows without residual blasts, in contrast to only 17% (0-37) reduction in hypoplastic marrows with ≥ 5% residual blasts (P < .001 for the difference between both groups). Bone marrow biopsies taken at the time of complete remission displayed a microvessel density in the same range as the controls. In conclusion, there is evidence of increased microvessel density in the bone marrow of patients with AML, which supports the hypothesis of an important role of angiogenesis in AML. Furthermore, these findings suggest that antiangiogenic therapy might constitute a novel strategy for the treatment of AML.

Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia

Blood ◽  
2000 ◽  
Vol 95 (8) ◽  
pp. 2637-2644 ◽  
Author(s):  
Teresa Padró ◽  
Sandra Ruiz ◽  
Ralf Bieker ◽  
Horst Bürger ◽  
Martin Steins ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Induction Chemotherapy ◽  
Microvessel Density ◽  
Myeloid Leukemia ◽  
Remission Induction ◽  
Bone Marrow Biopsies ◽  
Acute Myeloid

Abstract The importance of angiogenesis for the progressive growth and viability of solid tumors is well established. In contrast, only few data are available for hematologic neoplasms. To investigate the role of angiogenesis in acute myeloid leukemia (AML), bone marrow biopsies from 62 adults with newly diagnosed, untreated AML (day 0) were evaluated. Further studies were done after the completion of remission induction chemotherapy (day 16 of induction chemotherapy, n = 21; complete remission, n = 20). Microvessels were scored in at least 3 areas (×500 field, 0.126 mm2) of the highest microvessel density in representative sections of each bone marrow specimen using immunohistochemistry for von Willebrand factor and thrombomodulin. Microvessel counts were significantly higher in patients with AML (n = 62) compared with control patients (n = 22): median (interquartile range) 24.0 (21.0-27.8)/×500 field vs 11.2 (10.0-12.0)/×500 field, respectively (P &lt; .001). On day 16 of induction chemotherapy, microvessel density was reduced by 60% (44-66) (P &lt; .001) in hypoplastic marrows without residual blasts, in contrast to only 17% (0-37) reduction in hypoplastic marrows with ≥ 5% residual blasts (P &lt; .001 for the difference between both groups). Bone marrow biopsies taken at the time of complete remission displayed a microvessel density in the same range as the controls. In conclusion, there is evidence of increased microvessel density in the bone marrow of patients with AML, which supports the hypothesis of an important role of angiogenesis in AML. Furthermore, these findings suggest that antiangiogenic therapy might constitute a novel strategy for the treatment of AML.

ABR, a Novel Inducer Of Transcription Factor C/EBPα, Is Necessary For Myeloid Differentiation and a Prognostic Factor In Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3814-3814
Author(s):  
Carolina Yaeko Namasu ◽  
Dennis Gerloff ◽  
Alexander Arthur Wurm ◽  
Daniela Braeuer-Hartmann ◽  
Jens-Uwe Hartmann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Transcription Factor ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Myeloid Differentiation ◽  
U937 Cells ◽  
Acute Myeloid

Abstract ABR (Active BCR-related) is the only protein in humans and mice closely homologous to BCR. BCR acts as a tumor suppressor in different cancers, such as chronic myeloid leukemia and meningiomas. A putative anti-oncogenic role of ABR has been shown in tumors of the central nervous system, such as medulloblastoma and astrocytomas, in which deletion of ABR was found. However, the role of ABR in hematopoiesis or leukemia remains unclear. We hypothesized that ABR might be important for myelopoiesis via increasing the expression of C/EBPα, a transcription factor known to be pivotal for myeloid differentiation and functionally impaired in acute myeloid leukemia (AML). In fact, we found that ABR expression is dramatically down-regulated (Figure 1, p=0.01) in bone marrow from AML patients (pts; n=63) compared to bone marrow (BM) mononuclear cells from healthy donors (n=3). In agreement with this finding, Abr is significantly increased during M-CSF and G-CSF-stimulated differentiation of primary wild type mouse BM cells (p<0.05). Additionally, we observe that ABR is necessary for monopoiesis induced by PMA (phorbol 12-myristate 13-acetate), since ABR knockdown in leukemic U937 cells results in a significant reduction of about 50% in the number of CD11b+ cells 48h after PMA treatment (p<0.05). Enforced ABR expression induces C/EBPα and its targets M-CSFR, G-CSFR and microRNA (miR)-223 in U937 cells (p<0.01). Moreover, we prove that ABR knockdown prevents induction of CEBPA, M-CSFR and G-CSFR during PMA-mediated differentiation (p<0.05). ABR overexpression blocks cell-cycle progression and down-regulates the known C/EBPα inhibitor E2F1 (p<0.01) in U937 cells, indicating the functional role of ABR as tumor suppressor. Those data suggest that ABR might induce CEBPA expression via inhibition of cell cycle activator E2F1. Finally, we are the first to identify ABR as a good prognostic factor in AML: patients with high ABR expression (median cut) survive significantly longer after allogeneic hematopoietic stem cell transplantation (Figure 2, p=0.04, log-rank test). Furthermore, high ABR expression associates with a low percentage of blasts in the peripheral blood (p=0.006) and high levels of antileukemic miR-181a (p<0.001). In conclusion, these data indicate that ABR, a novel inducer of C/EBPα, is necessary for myelopoiesis and a prognostic factor in AML. Raising ABR levels might be a goal for future therapeutics in AML. Disclosures: No relevant conflicts of interest to declare.

Retrospective analysis of nadir bone marrow biopsies in predicting need for re-induction therapy in adult acute myeloid leukemia.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. e18509-e18509
Author(s):  
Paz J Vellanki ◽  
Kavya Kannamma Kannan ◽  
Margaret Murray ◽  
Bernard Tawfik ◽  
Allison Winter ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Retrospective Analysis ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Bone Marrow Biopsies ◽  
Acute Myeloid

scholarly journals Angiogenesis and Minimal Residual Disease in Patients with Acute Myeloid Leukemia

2020 ◽  
Author(s):  
Pardis Nematollahi ◽  
Azar Baradaran ◽  
Zahra Kasaei Koopaei ◽  
Hamidreza Sajjadieh
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Response To Treatment ◽  
Bone Marrow Biopsies ◽  
The Mean ◽  
Minimal Residual ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) is the most prevalent acute leukemia in adults. Bone marrow angiogenesis is crucial for pathogenesis of leukemia, and increasing bone marrow Mean Vascular Density (MVD) and level of angiogenesis factors are seen in patients with AML. Higher level of bone marrow MVD is associated with poor prognosis of AML according to previous studies. The present study aimed to compare bone marrow MVD in AML patients and controls and evaluate the relation between bone marrow MVD and number of residual blast cells after AML treatment. Materials and Methods: This study is a longitudinal study on AML patients who were admitted to Omid hospital. The bone marrow biopsies of patients with AML and patients with normal diagnosis –as control group- were taken from archives of pathology laboratory. Immunohistochemistry staining was used for all specimens by using thrombomodulin markers for calculating MVD. Flow cytometry findings of AML patients were assessed for percent of minimal residual disease (MRD) after AML treatment in AML patients group.                                                                 Results: In this study, 27 AML patients and 24 healthy individuals with mean age of 40.92±15.13 years were evaluated, of whom 56.86% were male. The mean bone marrow MVD was significantly higher in AML patients than controls. The mean bone marrow MVD was significantly higher in males and there was insignificant reverse correlation between bone marrow MVD and MRD. About 59.3% of AML patients had response to treatment and there was no significant relationship between MVD and response to treatment.                      Conclusion: Bone marrow MVD was higher in AML patients than controls and there was no remarkable relationship between bone marrow MVD and MRD and response to treatment.

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