scholarly journals Acute Myeloid Leukemia Patient-Derived Xenograft Models Generated with the Use of Immunodeficient NSG-SGM3 Mice

2021 ◽  
Vol 14 (4) ◽  
pp. 414-425
Author(s):  
Ekaterina Viktorovna Baidyuk ◽  
Ekaterina Vasilevna Belotserkovskaya ◽  
L.L. Girshova ◽  
V.A. Golotin ◽  
K.A. Levchuk ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tumor Cells ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Research Activity ◽  
Flow Cytofluorometry ◽  
National Medical ◽  
Patient Derived Xenograft ◽  
Xenograft Models ◽  
Acute Myeloid

Background. Up to the present the survival rates of acute myeloid leukemia (AML) patients have remained low. A successful AML management presupposes generating personalized models of the disease. The most promising research activity in this field is creation of AML patient-derived xenograft models using the advanced strain of immunodeficient humanized NSG-SGM3 mice. Aim. To generate AML patient-derived xenograft models using immunodeficient NSG-SGM3 mice. Materials & Methods. The creation of PDX models was based on bone marrow aspirates taken from 4 patients with newly diagnosed AML who were treated at the V.A. Almazov National Medical Research Center. Patient-derived tumor cells were transplanted to NSG-SGM3 mice. Test experiment consisted in injecting AML cells OCI-АМL2 and HL60 in NSG-SGM3 mice. The efficacy of tumor engraftment was evaluated in terms of physical condition of animals and laboratory tests (blood count, blood smear, PCR, and flow cytofluorometry). Results. The engraftment of applied tumor cells derived from AML patients was achieved in half (2 out of 4) of the transplanted tumor samples. In mice with successful transplantation leukocytosis was reported. Blast cells were identified in peripheral blood on Day 30 after transplantation. The mice with injected AML cells OCI-АМL2 and HL60 showed a more aggressive course of disease. Among tested approaches to evaluate tumor engraftment in mouse recipients, the PCR method was marked by highest sensitivity. Conclusion. The use of immunodeficient humanized NSG-SGM3 mice enables successful generation of AML patient-derived xenograft models.

scholarly journals Impact of CMV reactivation on relapse of acute myeloid leukemia after HCT is dependent on disease stage and ATG

2021 ◽  
Author(s):  
Amin T. Turki ◽  
Nikolaos Tsachakis-Mück ◽  
Saskia Leserer ◽  
Pietro Crivello ◽  
Tobias Liebregts ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Advanced Disease ◽  
Survival Rates ◽  
Disease Stage ◽  
The Impact ◽  
Cmv Reactivation ◽  
Acute Myeloid

Cytomegalovirus (CMV) reactivation is a frequent complication after allogeneic hematopoietic cell transplantation (HCT), whose impact on clinical outcome, in particular on leukemic relapse is controversial. We retrospectively analyzed 687 HCT recipients with acute myeloid leukemia (AML) and ciclosporin-based immunosuppression to better understand the differential impact of CMV on transplant outcomes depending on AML disease stage and in-vivo T-cell depletion with anti-thymocyte globulin (ATG). Without ATG, CMV reactivation associated with significantly reduced relapse, yet its effect was more pronounced for advanced disease AML (p=0.0002) than for patients in first complete remission (CR1, p=0.0169). Depending on the disease stage, ATG exposure abrogated relapse protection following CMV reactivation in advanced stages (p=0.796), while it inverted its effect into increased relapse for CR1 patients (p=0.0428). CMV reactivation was associated with significantly increased non-relapse mortality in CR1 patients without ATG (p=0.0187), but not in those with advanced disease and ATG. Following CMV reactivation, only patients with advanced disease had significantly higher event-free survival rates as compared to patients without CMV. Overall, our data suggest that both ATG and disease stage modulate the impact of post-HCT CMV reactivation in opposite directions, revealing a level of complexity that warrants future studies regarding the interplay between anti-virus and anti-tumor immunity.

scholarly journals IGFBP7 activates retinoid acid–induced responses in acute myeloid leukemia stem and progenitor cells

2020 ◽  
Vol 4 (24) ◽  
pp. 6368-6383
Author(s):  
Noortje van Gils ◽  
Han J. M. P. Verhagen ◽  
Arjo Rutten ◽  
Renee X. Menezes ◽  
Mei-Ling Tsui ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Induced Responses ◽  
Term Survival ◽  
All Trans Retinoic Acid ◽  
Stem And Progenitor Cells ◽  
Acute Myeloid

Abstract Treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) in combination with low doses of arsenic trioxide or chemotherapy leads to exceptionally high cure rates (>90%). ATRA forces APL cells into differentiation and cell death. Unfortunately, ATRA-based therapy has not been effective among any other acute myeloid leukemia (AML) subtype, and long-term survival rates remain unacceptably low; only 30% of AML patients survive 5 years after diagnosis. Here, we identified insulin-like growth factor binding protein 7 (IGFBP7) as part of ATRA-induced responses in APL cells. Most importantly, we observed that addition of recombinant human IGFBP7 (rhIGFBP7) increased ATRA-driven responses in a subset of non-APL AML samples: those with high RARA expression. In nonpromyelocytic AML, rhIGFBP7 treatment induced a transcriptional program that sensitized AML cells for ATRA-induced differentiation, cell death, and inhibition of leukemic stem/progenitor cell survival. Furthermore, the engraftment of primary AML in mice was significantly reduced following treatment with the combination of rhIGFBP7 and ATRA. Mechanistically, we showed that the synergism of ATRA and rhIGFBP7 is due, at least in part, to reduction of the transcription factor GFI1. Together, these results suggest a potential clinical utility of IGFBP7 and ATRA combination treatment to eliminate primary AML (leukemic stem/progenitor) cells and reduce relapse in AML patients.

Clinical relevance of P-glycoprotein expression in de novo acute myeloid leukemia

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 1997-2004 ◽  
Author(s):  
G Del Poeta ◽  
R Stasi ◽  
G Aronica ◽  
A Venditti ◽  
MC Cox ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Survival Rates ◽  
Disease Free Survival ◽  
Normal Karyotype ◽  
Free Survival ◽  
Negative Phenotype ◽  
Acute Myeloid

Abstract Cytofluorimetric detection of the multidrug resistance (MDR)-associated membrane protein (P-170) was performed at the time of diagnosis in 158 patients with acute myeloid leukemia using the C219 monoclonal antibody (MoAb). In 108 of these cases the JSB1 MoAb was also tested. An improved histogram subtraction analysis, based on curve fitting and statistical test was applied to distinguish antigen-positive from antigen-negative cells. A marker was considered positive when more than 20% of the cells were stained. At onset, P-170 was detected in 43% of cases with C219 and in 73% of cases with JSB1. There was a strict correlation between C219 and JSB1 positivity, as all C219+ cases were also positive for JSB1 MoAb (P < .001). No relationship was found between sex, age, organomegaly, and MDR phenotype. Significant correlation was found between CD7 and both C219 and JSB1 expression (P < .001 and .001, respectively). C219-negative phenotype was more often associated with a normal karyotype (24 of 55 with P = .030). Rhodamine 123 (Rh123) staining and flow cytometry analysis showed a significantly decreased mean fluorescence in 51 C219+ and 38 JSB1+ patients compared to 42 MDR negative ones (P < .001). The rate of first complete remission (CR) differed both between C219+ and C219- cases and between JSB+ and JSB- ones (30.9% v 71.1% and 35.4% v 93.1%, respectively, P < .001). Of the 21 C219+ patients who had yielded a first CR, 19 (90.4%) relapsed, compared with 28 of 64 (43.7%) C219- patients (P < .001). Of the 28 JSB1+ patients in first CR, 17 (60.7%) relapsed relative to 8 (29.6%) of 27 JSBI- ones (P = .021). A higher rate of relapses among MDR+ compared with MDR- patients was observed both for C219 and JSB1 MoAbs taken separately (C219 80% v 44%; JSB1 52% v 27%), with no relationship to age. The survival rates (Kaplan-Meyer method) were significantly shorter both in C219+ patients and in JSB1+ cases (P < .001). Disease-free survival curves followed this same trend. The combination (C219- JSB1+) identified a subset of patients with an intermediate outcome compared to C219 positive cases. The prognostic value of both markers (C219 and JSB1) was confirmed in multivariate analysis. These results suggest that the assessment of MDR phenotype by flow cytometry may be an important predictor of treatment outcome.

Sign in / Sign up

Export Citation Format

Share Document