scholarly journals Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Acute Myeloid Leukemia Progression and Drug Response

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2662-2662 ◽  
Author(s):  
Diana Passaro ◽  
Alessandro Di Tullio ◽  
Ander Abarrategi ◽  
Kevin Rouault-Pierre ◽  
Katie Foster ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Endothelial Cells ◽  
Acute Myeloid Leukemia ◽  
Treatment Response ◽  
Vascular Permeability ◽  
Myeloid Leukemia ◽  
Drug Response ◽  
Vascular Niche ◽  
Acute Myeloid

Abstract The biological and clinical behavior of hematological malignancies are not only determined by the properties of the leukemic cells themselves, but are also highly affected by interaction with the microenvironment, pointing to the existence of an active crosstalk between the two compartments. Previous studies showed that acute myeloid leukemia (AML) cells actively modify endothelial cells ex vivovia several pathways, mainly mediated by VEGF. However, as anti-VEGF therapies haven't produced successful results in clinical trials, an extensive study of the crosstalk between AML and the vascular niche in the bone marrow (BM) is required to provide new therapeutic strategies. In the present study we combined the use of mouse models of AML, human AML patient-derived xenografts (PDX) and direct analysis on patient-derived BM biopsies to provide a global, reliable picture of the bone marrow vasculature in AML disease. We found several abnormalities in the vascular architecture and function in PDX, such as increased number of endothelial cells, increased microvascular density (MVD), decreased vascular mean diameter and increased hypoxia. Furthermore, using two-photon confocal intravital imaging we witnessed increased vascular permeability upon AML engraftment, observed homogeneously among different PDX. Interestingly, induction chemotherapy failed to normalize the vascular permeability in the BM, despite significant reduction in AML engraftment. We identified increased nitric oxide (NO) as a major mediator of the AML-induced vascular leakiness in the BM. Increased levels of NO and activated NOS3 were found in PDX and in an independent cohort of patient-derived BM biopsies. Strikingly, inhibition of NO production using genetic and pharmacological approaches reduced the vascular permeability, potentiated the normal HSC function and significantly improved treatment response in PDX. These results strongly support the notion of a primary function of the vascular permeability in AML progression, drug response and in affecting normal stem cell function, and they call for clinical trials incorporating NOS inhibitors during the remission phase to target the abnormal vascular niche and improve the treatment response. Disclosures No relevant conflicts of interest to declare.

scholarly journals Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia

Cancer Cell ◽  
2017 ◽  
Vol 32 (3) ◽  
pp. 324-341.e6 ◽  
Author(s):  
Diana Passaro ◽  
Alessandro Di Tullio ◽  
Ander Abarrategi ◽  
Kevin Rouault-Pierre ◽  
Katie Foster ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Disease Progression ◽  
Vascular Permeability ◽  
Myeloid Leukemia ◽  
Drug Response ◽  
Bone Marrow Microenvironment ◽  
Acute Myeloid

Bone Marrow Endothelial Cells Protect Acute Myeloid Leukemia From Chemotherapy By Direct Contact: The BCAM/Laminin/VLA5 Axis As a Potential Therapeutic Target

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2546-2546 ◽  
Author(s):  
Leylah Drusbosky ◽  
Amy Meacham ◽  
Elizabeth Wise ◽  
Edward W Scott ◽  
Christopher R Cogle
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Acute Myeloid Leukemia ◽  
Adhesion Molecules ◽  
Therapeutic Target ◽  
Direct Contact ◽  
Myeloid Leukemia ◽  
Long Bones ◽  
Endosteal Niche ◽  
Acute Myeloid

Abstract Causes of refractory acute myeloid leukemia (AML) are unknown, but may be related to the bone marrow (BM) vascular network given the close relationship between hematopoiesis and the vasculature. We hypothesized that endothelial cells (ECs) provide a protective advantage to AML cells. To test this hypothesis, we first cultured human AML cells with and without primary bone marrow endothelial cells (BMECs). Co-cultures of AML cells and BMECs were then exposed to increasing doses of cytarabine chemotherapy. There was a 2-fold decrease in leukemia cell death of AML cells when adhered to BMECs compared to non-adhered (30% vs. 60%, P < 0.0001). Even irradiated BMECs protected AML cells from cytarabine chemotherapy. To identify adhesion molecules mediating this protective effect, we analyzed cell membranes and supernatants of the cytarabine-treated co-cultures using protein microarrays. After cytarabine exposure, the Lutheran blood group glycoprotein basal cell adhesion molecule (BCAM) was upregulated in both human AML cells and BMECs. Prior work has shown BCAM as a receptor for Laminin and VLA5. As AML cells are known to express VLA5, we hypothesized that blocking BCAM may represent a novel therapeutic strategy. Blocking BCAM with neutralizing antibodies resulted in a 75% increase in non-adherent AML cells. Together, these in vitro results support the concept that ECs may be a protective reservoir for AML cells, at a minimum by means of adhesion molecules. BCAM represents a viable target. Because of the complex nature of the leukemia microenvironment, we sought to test this concept in vivo. Prior intravital efforts have focused on calvaria bone, which may over-represent the endosteal niche and under-represent the vascular niche due to the very close approximation of bone surfaces. Therefore, we created an intravital animal model of human AML to track single AML cells in the bone marrow of mouse long bones. In brief, we irradiated NOD/scid/IL2Rγnull (NSG) mice, drilled a window on the tibia surface, xenotransplanted fluorescently tagged human AML cells via IV injection, and then analyzed the tibias by fluorescent microscopy for the presence of AML cells at various time points after transplant. Initially the AML cells homed to endosteal surfaces of the bone marrow as early as one day after transplant. Over time, the AML cells lining the endosteum remained as single cells or very small clusters of a few cells. However, in the central marrow region the AML cells proliferated into massive clusters around blood vessels. Ongoing experiments are being performed to determine the disruption and resurgence of AML cells after chemotherapy and blockade of adhesion molecules. In sum, ECs protect human AML cells from chemotherapy by direct contact and the BCAM/Laminin/VLA5 axis may be a therapeutic target. Using our unique intravital imaging model of bone marrow in long bones, the endosteal niche appears to be the first site of homing and engraftment while the vascular niche appears to be the site for leukemia proliferation/progression. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Decrease in Transfusion Needs in Patients with Higher-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia Treated with 5-Azacytidine. a Retrospective Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5608-5608
Author(s):  
Panagiotis Theodorou Diamantopoulos ◽  
Konstantinos Zervakis ◽  
Athanasios G. Galanopoulos ◽  
Panagiotis Bakarakos ◽  
Vasiliki Papadopoulou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Safety Data ◽  
Supportive Treatment ◽  
Efficacy And Safety ◽  
Red Blood Cell Transfusions ◽  
Acute Myeloid

Abstract Introduction The hypomethylating agent 5-azacytidine (AZA) has been the standard of care for higher risk Myelodysplastic Syndromes (MDS) for the last few years. Its efficacy has been proven in large clinical trials, and its safety has been shown to be superior to that of conventional treatments. We have conducted a retrospective study about the efficacy and safety of 5-azacytidine, as reported and analyzed in our center. Patients and Methods Forty four consecutive patients with MDS or Acute Myeloid Leukemia (AML) with 20-30% bone marrow blasts that were treated with AZA during the last 63 months were included in the study. The clinical and laboratory characteristics of the patients were recorded, and the efficacy and safety data were analyzed. Results The epidemiologic and hematologic characteristics of the patients are shown in Table 1. The median overall survival was 13 months (1-101) and there was no primary treatment failure (Table 2). Serious adverse events consisted mostly of neutropenic infections (blood stream and pneumonia) (Table 3). Discussion Treatment with AZA offered a favorable (complete and partial) response in 34.1% of the patients, and an overall survival of 13 months, with generally predictable toxicities, although hospitalization was frequently inevitable during the first treatment cycles, when supportive treatment was a significant part of the management. A valuable observation is that there was a considerable decrease in the patients’ transfusion needs following treatment (p<0.0001). Our results are consistent with the results of other clinical trials and point out the need for investigational 5-azacytidine combinations. Table 1. Epidemiologic and hematologic characteristics. Male: Female ratio 30:14 (2.1 : 1) Age, Median (Range) 73 (54-81) WHO classification of MDS/AML, N (%) RAEB-I RAEB-II RCMD-RS RCMD RARS CMML AML 9 (20.5) 18 (40.9) 2 (4.5) 3 (6.7) 1 (2.3) 4 (9.1) 7 (15.9) IPSS classification, N (%) Low Intermediate-1 Intermediate-2 High Not Applicable (AML) 0 (0) 3 (6.8) 29 (65.9) 5 (11.4) 7 (15.9) Complete Blood Count Parameters, Median (Range) Hemoglobin (g/dL) Absolute Neutrophil Count (x109/L) Platelet count (x109/L) 8.55 (4.5 - 12.5) 1.08 (0.0 – 16.3) 80.0 (2 – 820) Transfusion dependence, N (%) 39 (88.6) Transfusions per month, Median (Range) 3 (0 – 7) Table 2. Efficacy data AZA cycles, Median (Range) 5 (1-22) Actual AZA dose (mg/m2/cycle), Median (Range) 75 (59-75) Actual cycle duration (days), Median (Range) 28 (28-40) Dose reductions due to sustained neutropenia, N (%) 6 (13.6) Temporary AZA interruption, N (%) 26 (59.1) Reason Sustained cytopenia 10/26 (38.5) Neutropenic Infection 15/26 (57.7) Hemorrhagic Complication 1/26 (3.8) Permanent AZA discontinuation, N (%) 23/44 (52.3) Reason AML transformation 17/23 (73.9) Recurrent or severe infection 4/23 (17.4) Pyoderma gangrenosum 1/23 (4.3) Allogeneic Bone Marrow Transplantation 1/23 (4.3) AZA cycles till response (according to the IWG criteria), Median (Range) 4 (1 – 7) Response (IWG criteria), N (%) Complete response Partial response Stable disease Failure 7 (15.9) 8 (18.2) 29 (65.9) 0 (0) Overall survival (months), Median (Range) 13 (1 – 101) Post treatment transfusion dependence, N (%) 34 (77.3) Transfusions per month (post-treatment), Median (Range) 1 (0 – 5) Death rate, N (%) 29/44 (65.9) Cause of death, N (%) Infection Hemorrhage Cardiac dysrhythmia 24/29 (82.8) 3/29 (10.3) 2/29 (6.9) Table 3. Safety data Clinical adverse events, N (%) 29/44 (65.9) Neutropenic Infections 26/29 (89.7) Bloodstream Infection 9/26 (34.6) Lower respiratory infection 10/26 (38.5) Neutropenic Fever 8/26 (30.1) Septic shock 2/26 (7.7) Hemorrhagic events 2/29 (6.7) Cerebral hemorrhage (Grade 5) 1/2 (50.0) Epistaxis (Grade 3) 1/2 (50.0) Other (pyoderma gangrenosum) 1/29 (3.4) Laboratory incidents1, N (%) 44/44 (100) All grades Grades 3/4 Neutropenia 36/44 (81.8) 34/44 (77.3) Anemia 44/44 (100) 24/44 (54.5) Thrombocytopenia 31/44 (70.5) 21/44 (47.7) Supportive treatment (during AZA administration), N (%) GCSF administration 16/44 (36.4) Erythropoietin administration 7/44 (15.9) Red blood cell transfusions 39/44 (88.6) Red blood cell transfusions (units/cycle), Median (range) 3 (0-7) Pooled random donor platelet transfusions 17 (38.6) 1According to the CTCAE Version 4.0 Disclosures No relevant conflicts of interest to declare.

MicroRNA Signatures Associated with Cytogenetics and Outcome in Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 151-151
Author(s):  
Ramiro Garzon ◽  
Stefano Volinia ◽  
Chang G. Liu ◽  
Flavia Pichiorri ◽  
Tiziana Palumbo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Treatment Response ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Cytogenetic Abnormalities ◽  
Resistant Disease ◽  
Cd34 Cells ◽  
Differentiation Stage ◽  
Acute Myeloid

Abstract MicroRNAs are small non-coding RNAs of 19–25 nucleotides in length that are negative regulators of gene expression. Findings over the last few years indicate that microRNAs are involved in fundamental cellular process, including development and hematopoietic differentiation. Acute myeloid leukemia (AML) is a heterogeneous disorder that is characterized by proliferation of immature cells. Although there are well defined molecular subtypes of AML, the pathogenesis in the majority of cases is largely unknown. Focusing on known genes will not likely suffice to uncover the nature of the AML. The integration of a whole genome approach including non-coding RNA gene products may lead to an improve understanding of the biology of AML. Methods: To determine whether microRNAs are associated with known cytogenetic abnormalities and biological features in AML, we evaluated the microRNA expression profiles of 176 samples of adult AML with intermediate and poor risk cytogenetics and 10 CD34+ cells from healthy donors using a microarrays platform. After normalization, data were analyzed using significance analysis of microarrays and prediction analysis of microarrays software. An independent set of 28 patients with AML was used to validate the signatures using quantitative real time PCR. Treatment response was evaluated in 29 newly AML diagnosed patients 4 to 6 weeks after induction chemotherapy with idarubicin and cytarabine by bone marrow examination. Complete remission was defined as less than 5% blasts in the bone marrow. Otherwise it was categorized as resistant disease. Results: We found several microRNAs differentially expressed between CD34+ cells and all the AML samples. A subset of these microRNAs reflects the differentiation stage of the leukemias and correlate with the French-American-British classification of AML. Likewise, microRNAs are closely associated with the prevalent cytogenetic abnormalities. A common signature including the over expressed miR-20; miR-17, miR-25 and miR-191 are associated with short overall survival, while miR-29b is found down-regulated in patients with resistant disease. Furthermore, we proved experimentally that miR-29b regulates negatively MCL-1, a critical apoptosis regulator, which has been found up-regulated and associated with relapse and chemotherapy resistance in leukemia. Conclusions: MicroRNAs expression in AML is closely associated with differentiation stage, morphology and cytogenetics. A subset of MicroRNAs is correlated with survival and treatment response.

scholarly journals Comparative Analysis of Different Approaches to Measure Treatment Response in Acute Myeloid Leukemia

2012 ◽  
Vol 30 (29) ◽  
pp. 3625-3632 ◽  
Author(s):  
Hiroto Inaba ◽  
Elaine Coustan-Smith ◽  
Xueyuan Cao ◽  
Stanley B. Pounds ◽  
Sheila A. Shurtleff ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Treatment Response ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Multivariable Analysis ◽  
Long Term Outcome ◽  
Fusion Transcripts ◽  
Acute Myeloid

Purpose In acute myeloid leukemia (AML), initial treatment response by morphologic analysis of bone marrow predicts long-term outcome. Response can now be assessed by minimal residual disease (MRD) monitoring with flow cytometry or polymerase chain reaction (PCR). We determined the relation among the results of these approaches and their prognostic value. Patients and Methods In the multicenter AML02 study, follow-up bone marrow samples from 203 children and adolescents with newly diagnosed AML were examined by flow cytometry (n = 1,514), morphology (n = 1,382), and PCR amplification of fusion transcripts (n = 508). Results were correlated with treatment outcome. Results Among 1,215 samples with less than 5% leukemic myeloblasts by morphology, 100 (8.2%) were MRD positive (≥ 0.1%) by flow cytometry, whereas 96 (57.5%) of the 167 samples with ≥ 5% blasts were MRD negative. Virtually all (308 of 311; 99.0%) MRD-negative samples by PCR were also MRD negative by flow cytometry. However, only 19 (9.6%) of the 197 PCR-positive samples were flow cytometry positive, with analyses of AML1-ETO and CBFβ-MYH11 accounting for most discrepancies, whereas eight of 13 MLL-positive samples had detectable MRD by flow cytometry. MRD by flow cytometry after induction 1 or 2 predicted lower event-free survival and higher relapse rate (P < .001) and was an independent prognostic factor in a multivariable analysis; prediction was not improved by morphologic information or molecular findings. Conclusion In childhood AML, morphologic assessment of treatment response has limited value if MRD is measured by flow cytometry. MLL fusion transcripts can provide prognostic information in some patients, whereas monitoring of AML1-ETO and CBFβ-MYH11 transcripts is largely uninformative.

Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia.

1990 ◽  
Vol 8 (5) ◽  
pp. 813-819 ◽  
Author(s):  
B D Cheson ◽  
P A Cassileth ◽  
D R Head ◽  
C A Schiffer ◽  
J M Bennett ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
National Cancer Institute ◽  
Myeloid Leukemia ◽  
Phase Iii ◽  
Fab Classification ◽  
Phase Iii Trials ◽  
Routine Assessment ◽  
Acute Myeloid

The National Cancer Institute (NCI) sponsored a workshop to develop a set of standardized diagnostic and response criteria for acute myeloid leukemia (AML) clinical trials. The French-American-British (FAB) classification was retained for diagnosing AML, with the addition of patients with bone marrow morphologic features of a myelodysplastic syndrome and less than 30% bone marrow blasts, but with greater than or equal to 30% blasts in the peripheral blood. In this report, there are four important subgroups of AML not defined in the FAB classification that are discussed: undifferentiated acute leukemia, MO (AML lacking definitive myeloid differentiation by morphology or conventional cytochemistry but with ultrastructural or immunophenotypic evidence for AML), mixed lineage leukemia, and hypocellular AML. Definitions of response for clinical trials are presented to facilitate comparisons among different studies. Complete remission is considered the only response worth reporting in phase III trials, since lesser responses do not improve survival. Partial remissions may be of interest to identify active new agents in phase I and II studies. Monoclonal antibodies and cytogenetic studies are not part of the routine assessment of remission or reassessment at relapse, and their role in the evaluation of patients with AML is currently being evaluated in clinical trials. Although we recognize that some of the definitions in this report are arbitrary, generalized use of these guidelines will make results of clinical trials more comparable and interpretable.

scholarly journals In Vitro Characterization of Valproic Acid, ATRA, and Cytarabine Used for Disease-Stabilization in Human Acute Myeloid Leukemia: Antiproliferative Effects of Drugs on Endothelial and Osteoblastic Cells and Altered Release of Angioregulatory Mediators by Endothelial Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Hilde Kvestad ◽  
Lasse Evensen ◽  
James B. Lorens ◽  
Øystein Bruserud ◽  
Kimberley J. Hatfield
Keyword(s):  
Bone Marrow ◽  
Valproic Acid ◽  
Endothelial Cells ◽  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Stromal Cells ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Antiproliferative Effects ◽  
Acute Myeloid

The combined use of the histone deacetylase inhibitor valproic acid (VPA), the retinoic acid receptor-α agonist all-trans retinoic acid (ATRA), and the deoxyribonucleic acid polymerase-α inhibitor cytarabine (Ara-C) is now considered for disease-stabilizing treatment of acute myeloid leukemia (AML). Leukemogenesis and leukemia cell chemoresistance seem to be supported by neighbouring stromal cells in the bone marrow, and we have therefore investigated the effects of these drugs on primary human endothelial cells and the osteoblastic Cal72 cell line. The results show that VPA and Ara-C have antiproliferative effects, and the antiproliferative/cytotoxic effect of Ara-C was seen at low concentrations corresponding to serum levels found during low-dose in vivo treatment. Furthermore, in functional assays of endothelial migration and tube formation VPA elicited an antiangiogenic effect, whereas ATRA elicited a proangiogenic effect. Finally, VPA and ATRA altered the endothelial cell release of angiogenic mediators; ATRA increased levels of CXCL8, PDGF-AA, and VEGF-D, while VPA decreased VEGF-D and PDGF-AA/BB levels and both drugs reduced MMP-2 levels. Several of these mediators can enhance AML cell proliferation and/or are involved in AML-induced bone marrow angiogenesis, and direct pharmacological effects on stromal cells may thus indirectly contribute to the overall antileukemic activity of this triple drug combination.

High Serum Level of Placental Growth Factor (PlGF) Predicts Adverse Overall Survival in Patients with Acute Myeloid Leukemia Treated with Standard Chemotherapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3972-3972
Author(s):  
Agnieszka Wierzbowska ◽  
Anna Krawczynska ◽  
Ewa Wawrzyniak ◽  
Agnieszka Pluta ◽  
Anna Wolska ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Endothelial Cells ◽  
Acute Myeloid Leukemia ◽  
Growth Factor ◽  
Myeloid Leukemia ◽  
Univariate Analysis ◽  
Placental Growth Factor ◽  
Healthy Controls ◽  
Acute Myeloid

Abstract Background: Angiogenesis plays an important role in the pathogenesis of acute myeloid leukemia (AML) and vascular endothelial growth factor (VEGF) is an essential positive regulator of this process. Placental growth factor (PlGF) is a member of VEGF family that exerts its angiogenic action by synergizing with VEGF. There is also evidence that PlGF may be survival factor for angiogenic endothelial cells. The role of PlGF in patients with acute leukemia have not been investigated at all. Material and methods: We measured the plasma concentrations of VEGF and PlGF in 61 patients with newly diagnosed AML and 22 healthy controls using the ELISA assay. Additionally, in AML patients we correlated the plasma levels of angiogenic cytokines with the number of viable (CEC) and apoptotic (CECAnnV+) circulating endothelial cells, known prognostic factors, response to induction therapy as well as overall survival (OS). The AML group consisted of 34 women and 27 men with a median age of 49 years (range 25–76 years). All patient received standard induction chemotherapy (according to 3+7 protocol). Statistical analysis included the following variables: VEGF and PlGF levels, age, sex, performance status, cytogenetic risk group according SWOG, presence of multilineage dysplasia, WBC and PLT count, hemoglobin level, LDH activity, % of bone marrow blasts and CEC as well as CECAnnV+ number. Results: The PlGF and VEGF median levels (23,6 pg/ml and 45,1 pg/ml respectively) were significantly higher in the AML at diagnosis than in the healthy subjects (9,5 pg/ml; p&lt;0,0001 and 25,2 pg/ml; p&lt;0,03 respectively). Moreover, the VEGF level at diagnosis in patients who did not respond to induction chemotherapy was significantly higher than in patients who achieved complete remission (CR) (84,7 vs 31,2 pg/ml; p&lt;0,01). The significant negative correlation between the VEGF and percentage of apopototic CECAnnV+ was also observed. Median follow-up was 12,1 months (range: 1– 43 months). 50 patients (82%) achieved CR. The CR rate in low and high VEGF expressors was respectively 86% and 70% (p=0.07). The CR rate in high- and low PlGF expressors did not differ significantly (74% and 80% respectively). In univariate analysis poor cytogenetics was the only factor associated with increased risk of treatment failure. The median time of OS in analysed group was 15 months. In the univariate analysis high (over median) PlGF levels was associated with shorter OS (p=0.005) (Figure1). Shorter OS was also associated with age&gt;40 years (p=0.009), failure to achieve CR (p=0.009) and higher (&gt;50%) bone marrow infiltration with leukemic blasts (p=0.005). In the multivariate Cox proportional hazard model the elevated PlGF plasma level was strongly associated with shorter OS (p&lt;0.007). The other factors found to influence shorter OS were: high bone marrow infiltration with leukemic blasts (p=0.02), age&gt;40 years (p=0.04), failure to achieve CR (p=0.04). Conclusions: In conclusion we can state that the high plasma concentration of PlGF is associated with poor prognosis in AML patients. Observed in our study significantly higher PlGF level in AML patients compared to healthy controls may indicate that this angiogenic cytokine plays an important, independent of VEGF role in pathogenesis of AML Figure Figure

Just say NO to leaky bone marrow vasculature in AML

2017 ◽  
Vol 9 (410) ◽  
pp. eaap8163
Author(s):  
Brian A. Jonas
Keyword(s):  
Nitric Oxide ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Treatment Response ◽  
Myeloid Leukemia ◽  
No Production ◽  
Vascular Architecture ◽  
And Function ◽  
Acute Myeloid

Inhibition of nitric oxide (NO) production improved treatment response and normalized NO-mediated alterations in bone marrow vascular architecture and function in acute myeloid leukemia.

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