scholarly journals Immunoexpression of CD34, CD117, and p53 in Hypocellular Bone Marrow Disorders

2021 ◽  
Author(s):  
Pooja Sharma ◽  
Anshu Palta ◽  
Anita Tahlan ◽  
Manveen Kaur ◽  
Ram Singh
Keyword(s):  
Bone Marrow ◽  
Myeloid Leukemia ◽  
The Other ◽  
Immunohistochemical Expression ◽  
Cd34 Cells ◽  
Significant Difference ◽  
Blast Count ◽  
Bone Marrow Disorders ◽  
Acute Myeloid

Abstract Objectives Hypocellular bone marrow (BM) disorders comprise heterogeneous entities associated with peripheral cytopenias and decreased production of hematopoietic cells in BM. This study was undertaken to analyze immunohistochemical expression of CD34, CD117, and p53 in morphologically diagnosed patients of hypocellular BM (aplastic anemia [AA], hypocellular myelodysplastic syndrome [h-MDS], and hypocellular acute myeloid leukemia [h-AML]). Materials and Methods BM specimens were obtained from patients presenting with pancytopenia/bicytopenia. On 30 patients diagnosed as hypocellular BM, immunohistochemistry (IHC) for CD34, CD117, and p53 was performed. Results BM cellularity was < 30% in all (100%) patients. Blast count was increased in h-MDS and h-AML. Features of dysplasia were noted in six (20%) patients. Out of these, three patients were diagnosed as h-MDS having bilineage/trilineage dysplasia, and the other three patients were of AA (11.5% patients) displaying only dyserythropoiesis. On IHC, percentage of BM CD34+ cells was increased in h-MDS+ h-AML (3.87 ± 0.86) as compared with AA (0.19 ± 0.15) and controls (0.81 ± 0.21), p = 0.01. Percentage of BM p53+ cells was also increased in h-MDS+ h-AML (2.9 ± 2.07) as compared with AA and controls, which did not show any p53+ cells, p = 0.0. No statistically significant difference was observed in the expression of CD117 in h-MDS+ h-AML (4.95 ± 3.40) compared with AA (4.49 ± 1.07), p = 0.99. Conclusion The study demonstrates the usefulness of CD34 and p53 immunoexpression as an important ancillary method in distinguishing various hypocellular BM disorders, especially h-MDS and AA. However, the role of CD117 remains unclear and needs to be evaluated further by larger studies.

MN1 Expression Predicts Prognosis of Acute Myeloid Leukemia with Normal Cytogenetics.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2351-2351
Author(s):  
Michael Heuser ◽  
Gernot Beutel ◽  
Jürgen Krauter ◽  
Nils von Neuhoff ◽  
Brigitte Schlegelberger ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Performance Status ◽  
Ecog Performance Status ◽  
Free Survival ◽  
Cd34 Cells ◽  
Significant Difference ◽  
Normal Cytogenetics ◽  
Acute Myeloid

Abstract Cytogenetic aberrations are important prognostic factors in acute myeloid leukemia (AML). However, approximately half of adult AML patients lack cytogenetic abnormalities and identification of predictive molecular markers might improve therapy. Fusion of meningioma-1 (MN1) to TEL (ETV6) has been found in AML and MDS with t(12;22)(p13;q11). However, expression levels of MN1 have not been reported previously in AML. We evaluated MN1 expression as a prognostic marker in 142 AML patients aged 18–60 years with normal cytogenetics, who were uniformely treated according to the AML-SHG 1/99 trial. Patients received intensive, cytarabine-based induction and consolidation treatment including allogeneic progenitor cell transplantation if an HLA-compatible sibling was available, or in case of relapse. Specimens were obtained at diagnosis, and routine cytogenetic, FLT3-mutation, and MLL-PTD analyses were performed. MN1 expression was quantified by real-time RT-PCR on a LightCycler using QuantiTect SYBR Green. AML samples were dichotomized at the median value resulting in two groups: a low MN1 group and a high MN1 group. Baseline characteristics and outcome parameters were compared between these two groups. In addition, CD34+ cells were immunomagnetically enriched from mobilized blood of a healthy donor using MACS CD34 isolation kit. Cells were cultured in IMDM medium with various cytokines including either G-CSF, M-CSF or EPO. At various time points, cells were harvested and analyzed for MN1 expression. There were no significant differences between low MN1 and high MN1 expressing patients with respect to age, gender, ECOG performance status, diagnosis of de novo or secondary AML, FAB morphology, white blood cell count, percentage of blasts in blood or bone marrow, FLT3 mutations, or MLL-PTD. Low MN1 expressing patients significantly more often achieved a good response to the first course of induction treatment defined as blasts in bone marrow below 5%, no blasts in peripheral blood, and no extramedullary manifestation at day 15 compared to high MN1 expressing patients (87.3% vs. 71.8%, p=.02). There was no significant difference for remission status between the two groups. High MN1 expression predicted significantly shorter event-free survival (19% vs. 45.8% at 3 years, log-rank p=.0009), shorter relapse-free survival (23% vs. 52.8% at 3 years, log-rank p=.001), and shorter overall survival (38.2% vs. 58.8% at 3-years, log-rank p=.03). The high MN1 group relapsed significantly more often compared to the low MN1 group (56.7% vs. 35%, p=.02), and thus received an allogeneic transplant significantly more often (50.7% vs. 33.8%, p=.04). In multivariate analysis including known risk factors only MN1 expression, age (above the median compared to below the median age), and ECOG performance status (0 or 1 compared to 2) remained significant (hazard ratio: 2 (p=.01), 2.1 (p=.005) and 2.8 (p=.005), respectively). MN1 expression in CD34+ cells was 37-fold higher compared to the CD34− cell fraction. However, by in vitro differentiation of CD34+ cells using various cytokines including either G-CSF, M-CSF or EPO, MN1 expression dropped to levels found in the CD34− fraction within 7 days of culture. In conclusion, high MN1 expression predicts adverse prognosis and may define an important risk factor in AML with normal cytogenetics. Its upregulation in hematopoietic progenitor cells hints at a functional role of MN1 in blocking differentiation.

Bone Marrow Small Adipocytes in Acute Myeloid Leukemia Correlate with Prognosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2874-2874
Author(s):  
Wei Lu ◽  
Jun Shi
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Solid Tumors ◽  
Myeloid Leukemia ◽  
Prognostic Impact ◽  
Biopsy Specimens ◽  
Brown Adipose ◽  
Significant Difference ◽  
Acute Myeloid

Abstract Introduction: Adipocytes have a substantial effect on the outcome and progression of certain solid tumors. However, little attention has been paid to the role of bone marrow (BM) adipocytes in acute myeloid leukemia (AML) because it is difficult to observe adipocytes through clinical BM aspiration. Although it was reported that adipocytes affected the behavior of leukemia cells in vitro, there is still no direct in vivo evidence. In the present study, we investigated the influence of adipocytes by focusing on their changing size in BM from primary AML patients. Methods: We retrospectively analyzed the biopsy specimens of BM from 70 patients with newly diagnosed AML and 70 controls with lymphoma or solid tumors without infiltration of BM. The size and type of adipocytes were analyzed for average diameter (Ad.Dm) and area (Ad.Ar) by tracing each individual adipocyte with Image-Pro Plus 5.1. Then, AML patients were further divided into 32 patients with continuous complete remission and 38 patients who were refractory based on the treatment effects. Adipocyte number (Ad.N; per square millimeter) and the percentage of adipocyte volume per tissue volume (Ad.V/TV) were compared between these two groups. Furthermore, the prognostic impact of adipocytes on the overall survival (OS) and relapse-free survival (RFS) in AML patients was analyzed by Cox regression analysis and Kaplan-Meier curves. Finally, the phenotype of adipocytes was determined by immunohistochemistry of UCP-1 and Perilipin1 to further explore the possible mechanism of the effect of adipocytes on the prognosis. Results: The Ad.Dm and Ad.Ar in BM from AML patients were 38.3±14.7 µm and 559.4±271.9 µm2, respectively, and both values were significantly smaller than those for the controls (P<0.001). The Ad.Dm exhibited no relation to the number of blasts in BM, indicating that the decreased size of adipocytes in AML cannot be attributed to extensive marrow blasts. Adipocytes were classified as small, medium and large adipocytes according to the frequency distribution of Ad.Dm in BM from controls. A significant difference was detected only in the proportion of small adipocytes (Ad.Dm<42.6 µm) between AML patients and controls (43.9% vs 25%, P=0.005). Furthermore, the Ad.V/TV and Ad.N of the adipocytes in the refractory group were 6.70±3.18% and 31.56±11.72/mm2, respectively, which were significantly higher than those of the remission subjects (P<0.001). This outcome prompted us to further analyze the role of small adipocytes in AML. Patients with Ad.V/TV of small adipocytes≤ 2.3% exhibited a longer OS than patients with Ad.V/TV of small adipocytes >2.3% (P<.001). Similarly, the subjects with Ad.N of small adipocytes <10.6/mm2 (P<.001) had a longer OS. Meanwhile, for the remission AML patients, those with Ad.V/TV of small adipocytes ≤2.5% had a shorter RFS than patients with Ad.V/TV of small adipocytes >2.5% (P<.001), and similar significant differences were also found between patients with Ad.N of small adipocytes ≥9.2/mm2 and Ad.N of small adipocytes <9.2/mm2(P<.001). In the biopsy specimens of BM, the subgroup of small adipocytes exhibited expression of Perilipin1 but not mitochondrial membrane protein UCP-1. Combination with the unilocular lipid droplets in adipocytes indicated that small adipocytes did not play a role in the conversion to brown adipose tissue. Conclusions: We first defined a subpopulation of small adipocytes in BM and demonstrated that only these cells but not all adipocytes were related to a poor prognosis in AML patients. The morphological changes of marrow adipocytes could be helpful to judge the prognosis of leukemia and could lead to other therapeutic perspectives. Disclosures No relevant conflicts of interest to declare.

scholarly journals Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Yiyi Yao ◽  
Fenglin Li ◽  
Jiansong Huang ◽  
Jie Jin ◽  
Huafeng Wang
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chemotherapy Resistance ◽  
Bone Marrow Microenvironment ◽  
Cytotoxic Effects ◽  
High Relapse Rate ◽  
Underlying Mechanisms ◽  
Acute Myeloid

AbstractDespite the advances in intensive chemotherapy regimens and targeted therapies, overall survival (OS) of acute myeloid leukemia (AML) remains unfavorable due to inevitable chemotherapy resistance and high relapse rate, which mainly caused by the persistence existence of leukemia stem cells (LSCs). Bone marrow microenvironment (BMM), the home of hematopoiesis, has been considered to play a crucial role in both hematopoiesis and leukemogenesis. When interrupted by the AML cells, a malignant BMM formed and thus provided a refuge for LSCs and protecting them from the cytotoxic effects of chemotherapy. In this review, we summarized the alterations in the bidirectional interplay between hematopoietic cells and BMM in the normal/AML hematopoietic environment, and pointed out the key role of these alterations in pathogenesis and chemotherapy resistance of AML. Finally, we focused on the current potential BMM-targeted strategies together with future prospects and challenges. Accordingly, while further research is necessary to elucidate the underlying mechanisms behind LSC–BMM interaction, targeting the interaction is perceived as a potential therapeutic strategy to eradicate LSCs and ultimately improve the outcome of AML.

scholarly journals Gpr44 Mediates the Selenium-Dependent Anti-Leukemic Effect in Acute Myeloid Leukemia

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1835-1835
Author(s):  
Fenghua Qian ◽  
Fenghua Qian ◽  
Diwakar Tukaramrao ◽  
Jiayan Zhou ◽  
Nicole Palmiero ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Murine Model ◽  
Myeloid Leukemia ◽  
Hematopoietic Stem ◽  
Cell Counts ◽  
Pparγ Agonist ◽  
Acute Myeloid

Abstract Objectives The relapse of acute myeloid leukemia (AML) remains a significant concern due to persistent leukemia stem cells (LSCs) that are not targeted by existing therapies. LSCs show sensitivity to endogenous cyclopentenone prostaglandin J (CyPG) metabolites that are increased by dietary trace element selenium (Se), which is significantly decreased in AML patients. We investigated the anti-leukemic effect of Se supplementation in AML via mechanisms involving the activation of the membrane-bound G-protein coupled receptor 44 (Gpr44) and the intracellular receptor, peroxisome proliferator-activated receptor gamma (PPARγ), by endogenous CyPGs. Methods A murine model of AML generated by transplantation of hematopoietic stem cells (HSCs- WT or Gpr44−/−) expressing human MLL-AF9 fusion oncoprotein, in the following experiments: To investigate the effect of Se supplementation on the outcome of AML, donor mice were maintained on either Se-adequate (Se-A; 0.08–0.1 ppm Se) or Se-supplemented (Se-S; 0.4 ppm Se) diets. Complete cell counts in peripheral blood were analyzed by hemavet. LSCs in bone marrow and spleen were analyzed by flow cytometry. To determine the role of Gpr44 activation in AML, mice were treated with Gpr44 agonists, CyPGs. LSCs in bone marrow and spleen were analyzed. Mice transplanted with Gpr44−/- AML cells were compared with mice transplanted with wild type AML cells and the progression of the disease was followed as above. To determine the role of PPARγ activation in AML, PPARγ agonist (Rosiglitazone, 6 mg/kg, i.p, 14 d) and antagonist (GW9662, 1 mg/kg, i.p. once every other day, 7 injections) were applied to Se-S mice transplanted with Gpr44−/- AML cells and disease progression was followed. Results Se supplementation at supraphysiological levels alleviated the disease via the elimination of LSCs in a murine model of AML. CyPGs induced by Se supplementation mediate the apoptosis in LSCs via the activation of Gpr44 and PPARγ. Conclusions Endogenous CyPGs produced upon supplementation with Se at supraphysiological levels improved the outcome of AML by targeting LSCs to apoptosis via the activation of two receptors, Gpr44 and PPARg. Funding Sources NIH DK 07,7152; CA 175,576; CA 162,665. Office of Dietary Supplements, USDA Hatch funds PEN04605, Accession # 1,010,021 (KSP, RFP).

scholarly journals Silencing long non-coding RNA XIST suppresses drug resistance in acute myeloid leukemia through down-regulation of MYC by elevating microRNA-29a expression

2020 ◽  
Vol 26 (1) ◽  
Author(s):  
Chong Wang ◽  
Lingling Li ◽  
Mengya Li ◽  
Weiqiong Wang ◽  
Yanfang Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Cellular Viability ◽  
Down Regulation ◽  
Acute Myeloid

Abstract Background Long non-coding RNAs (lncRNAs) are biomarkers participating in multiple disease development including acute myeloid leukemia (AML). Here, we investigated molecular mechanism of X Inactive-Specific Transcript (XIST) in regulating cellular viability, apoptosis and drug resistance in AML. Methods XIST, miR-29a and myelocytomatosis oncogene (MYC) expression in AML bone marrow cells collected from 62 patients was evaluated by RT-qPCR and Western blot analysis. Besides, the relationship among XIST, miR-29a and MYC was analyzed by dual luciferase reporter assay, RIP, and RNA pull down assays. AML KG-1 cells were treated with anti-tumor drug Adriamycin. The role of XIST/miR-29a/MYC in cellular viability, apoptosis and drug resistance in AML was accessed via gain- and loss-of-function approaches. At last, we evaluated role of XIST/miR-29a/MYC on tumorigenesis in vivo. Results XIST and MYC were up-regulated, and miR-29a was down-regulated in AML bone marrow cells. Silencing XIST inhibited cellular activity and drug resistance but promoted cellular apoptosis of KG-1 cells by down-regulating MYC. XIST inhibited miR-29a expression to up-regulate MYC. Moreover, silencing XIST inhibited tumorigenesis of AML cells in vivo. Conclusions Overall, down-regulation of XIST decreased MYC expression through releasing the inhibition on miR-29a, thereby reducing drug resistance, inhibiting viability and promoting apoptosis of AML cells.

scholarly journals Fatal Idiopathic Hyperammonemia after Induction Chemotherapy for Acute Myeloid Leukemia

2020 ◽  
Vol 2020 ◽  
pp. 1-4
Author(s):  
Christophe Angelo ◽  
Marie-Françoise Vincent ◽  
Mina Komuta ◽  
Philippe Hantson ◽  
Nicole Straetmans ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Care Management ◽  
Fatal Complication ◽  
Intensive Care Management ◽  
Brain Dead ◽  
Acute Myeloid

Idiopathic hyperammonemia is a rare but potentially fatal complication occurring in patients with acute leukemia or bone marrow transplantation. The role of some specific anticancer drugs may be discussed, but the etiology of hyperammonemia is often multifactorial. We report the case of a 40-year-old woman who developed fatal idiopathic hyperammonemia two weeks after induction chemotherapy with idarubicin-aracytine for acute myeloid leukemia. Despite intensive care management and extrarenal epuration, the patient was declared brain dead two days after hyperammonemia onset.

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