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.

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.

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 The Bone Marrow Microenvironment Mechanisms in Acute Myeloid Leukemia

2021 ◽  
Vol 9 ◽  
Author(s):  
Débora Bifano Pimenta ◽  
Vanessa Araujo Varela ◽  
Tarcila Santos Datoguia ◽  
Victória Bulcão Caraciolo ◽  
Gabriel Herculano Lopes ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Microenvironment ◽  
Cellular Mechanisms ◽  
Cytokines And Chemokines ◽  
New Perspective ◽  
Basic Studies ◽  
And Function ◽  
Acute Myeloid

Bone marrow (BM) is a highly complex tissue that provides important regulatory signals to orchestrate hematopoiesis. Resident and transient cells occupy and interact with some well characterized niches to produce molecular and cellular mechanisms that interfere with differentiation, migration, survival, and proliferation in this microenvironment. The acute myeloid leukemia (AML), the most common and severe hematological neoplasm in adults, arises and develop in the BM. The osteoblastic, vascular, and reticular niches provide surface co-receptors, soluble factors, cytokines, and chemokines that mediate important functions on hematopoietic cells and leukemic blasts. There are some evidences of how AML modify the architecture and function of these three BM niches, but it has been still unclear how essential those modifications are to maintain AML development. Basic studies and clinical trials have been suggesting that disturbing specific cells and molecules into the BM niches might be able to impair leukemia competencies. Either through niche-specific molecule inhibition alone or in combination with more traditional drugs, the bone marrow microenvironment is currently considered the potential target for new strategies to treat AML patients. This review describes the cellular and molecular constitution of the BM niches under healthy and AML conditions, presenting this anatomical compartment by a new perspective: as a prospective target for current and next generation therapies.

Enasidenib: First Mutant IDH2 Inhibitor for the Treatment of Refractory and Relapsed Acute Myeloid Leukemia

2019 ◽  
Vol 18 (14) ◽  
pp. 1936-1951 ◽  
Author(s):  
Raghav Dogra ◽  
Rohit Bhatia ◽  
Ravi Shankar ◽  
Parveen Bansal ◽  
Ravindra K. Rawal
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Adverse Effects ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
White Blood Cells ◽  
Phase Iii ◽  
Acute Myeloid

Background: Acute myeloid leukemia is the collective name for different types of leukemias of myeloid origin affecting blood and bone marrow. The overproduction of immature myeloblasts (white blood cells) is the characteristic feature of AML, thus flooding the bone marrow and reducing its capacity to produce normal blood cells. USFDA on August 1, 2017, approved a drug named Enasidenib formerly known as AG-221 which is being marketed under the name Idhifa to treat R/R AML with IDH2 mutation. The present review depicts the broad profile of enasidenib including various aspects of chemistry, preclinical, clinical studies, pharmacokinetics, mode of action and toxicity studies. Methods: Various reports and research articles have been referred to summarize different aspects related to chemistry and pharmacokinetics of enasidenib. Clinical data was collected from various recently published clinical reports including clinical trial outcomes. Result: The various findings of enasidenib revealed that it has been designed to allosterically inhibit mutated IDH2 to treat R/R AML patients. It has also presented good safety and efficacy profile along with 9.3 months overall survival rates of patients in which disease has relapsed. The drug is still under study either in combination or solely to treat hematological malignancies. Molecular modeling studies revealed that enasidenib binds to its target through hydrophobic interaction and hydrogen bonding inside the binding pocket. Enasidenib is found to be associated with certain adverse effects like elevated bilirubin level, diarrhea, differentiation syndrome, decreased potassium and calcium levels, etc. Conclusion: Enasidenib or AG-221was introduced by FDA as an anticancer agent which was developed as a first in class, a selective allosteric inhibitor of the tumor target i.e. IDH2 for Relapsed or Refractory AML. Phase 1/2 clinical trial of Enasidenib resulted in the overall survival rate of 40.3% with CR of 19.3%. Phase III trial on the Enasidenib is still under process along with another trial to test its potency against other cell lines. Edasidenib is associated with certain adverse effects, which can be reduced by investigators by designing its newer derivatives on the basis of SAR studies. Hence, it may come in the light as a potent lead entity for anticancer treatment in the coming years.

scholarly journals The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities

2021 ◽  
Vol 22 (13) ◽  
pp. 6857
Author(s):  
Samantha Bruno ◽  
Manuela Mancini ◽  
Sara De Santis ◽  
Cecilia Monaldi ◽  
Michele Cavo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Cell Fate ◽  
Myeloid Leukemia ◽  
Hematologic Malignancy ◽  
Bone Marrow Microenvironment ◽  
Metabolic Adaptation ◽  
Cell Fate Decisions ◽  
Wide Range ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a hematologic malignancy caused by a wide range of alterations responsible for a high grade of heterogeneity among patients. Several studies have demonstrated that the hypoxic bone marrow microenvironment (BMM) plays a crucial role in AML pathogenesis and therapy response. This review article summarizes the current literature regarding the effects of the dynamic crosstalk between leukemic stem cells (LSCs) and hypoxic BMM. The interaction between LSCs and hypoxic BMM regulates fundamental cell fate decisions, including survival, self-renewal, and proliferation capacity as a consequence of genetic, transcriptional, and metabolic adaptation of LSCs mediated by hypoxia-inducible factors (HIFs). HIF-1α and some of their targets have been associated with poor prognosis in AML. It has been demonstrated that the hypoxic BMM creates a protective niche that mediates resistance to therapy. Therefore, we also highlight how hypoxia hallmarks might be targeted in the future to hit the leukemic population to improve AML patient outcomes.

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