scholarly journals Resistance Mechanisms to SYK Inhibition in Acute Myeloid Leukemia

2019 ◽  
Vol 10 (2) ◽  
pp. 214-231 ◽  
Author(s):  
Anjali Cremer ◽  
Jana M. Ellegast ◽  
Gabriela Alexe ◽  
Elizabeth S. Frank ◽  
Linda Ross ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Resistance Mechanisms ◽  
Acute Myeloid

scholarly journals Expression of some ATP-binding cassette transporters in acute myeloid leukemia

2017 ◽  
Vol 9 (4) ◽  
Author(s):  
Antonella Maria Salvia ◽  
Flavia Cuviello ◽  
Sabrina Coluzzi ◽  
Roberta Nuccorini ◽  
Immacolata Attolico ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Abc Transporters ◽  
Healthy Subjects ◽  
Myeloid Leukemia ◽  
Resistance Mechanisms ◽  
Atp Binding ◽  
Atp Binding Cassette Transporters ◽  
Acute Myeloid ◽  
Atp Binding Cassette

Hematopoietic cells express ATP binding cassette (ABC) transporters in relation to different degrees of differentiation. One of the known multidrug resistance mechanisms in acute myeloid leukemia (AML) is the overexpression of efflux pumps belonging to the superfamily of ABC transporters such as ABCB1, ABCG2 and ABCC1. Although several studies were carried out to correlate ABC transporters expression with drug resistance, little is known about their role as markers of diagnosis and progression of the disease. For this purpose we investigated the expression, by real-time PCR, of some ABC genes in bone marrow samples of AML patients at diagnosis and after induction therapy. At diagnosis, ABCG2 was always down-regulated, while an up regulated trend for ABCC1 was observed. After therapy the examined genes showed a different expression trend and approached the values of healthy subjects suggesting that this event could be considered as a marker of AML regression. The expression levels of some ABC transporters such as ABCC6, seems to be related to gender, age and to the presence of FLT3/ITD gene mutation.

Multidrug resistance protein attenuates gemtuzumab ozogamicin–induced cytotoxicity in acute myeloid leukemia cells

Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1466-1473 ◽  
Author(s):  
Roland B. Walter ◽  
Brian W. Raden ◽  
Tom C. Hong ◽  
David A. Flowers ◽  
Irwin D. Bernstein ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multidrug Resistance ◽  
Myeloid Leukemia ◽  
Resistance Mechanisms ◽  
Gemtuzumab Ozogamicin ◽  
Multidrug Resistance Protein ◽  
Acute Myeloid Leukemia Cells ◽  
Additional Resistance ◽  
Resistance Protein ◽  
Acute Myeloid

Abstract Gemtuzumab ozogamicin (GO) is a novel immunoconjugate therapy for acute myeloid leukemia (AML). P-glycoprotein (Pgp) confers resistance to GO and is associated with a worse clinical response. To address whether multidrug resistance protein (MRP) affects GO susceptibility, we characterized Pgp, MRP1, and MRP2 expression in CD33+ cell lines and CD33+ AML samples and analyzed the effect of the Pgp inhibitor cyclosporine (CSA) and the MRP inhibitor MK-571 on GO-induced cytotoxicity. MRP1, but not MRP2, expression correlated with MRP activity. MK-571 enhanced GO-induced cytotoxicity in Pgpnegative/MRP-positive NB4 and HL-60 cells. CSA, but not MK-571 alone, restored GO susceptibility in Pgp-positive/MRP-positive TF1 cells; however, MK-571 enhanced cytotoxicity in the presence of CSA. All patient samples exhibited MRP activity, and 17 of 23 exhibited Pgp activity. CSA increased GO-induced cytotoxicity in 12 Pgp-positive samples, whereas MK-571 alone was effective in only one sample with minimal Pgp activity. In 3 Pgp-positive/MRP-positive samples, MK-571 enhanced GO-induced cytotoxicity in the presence of CSA. Thus, MRP1 may attenuate susceptibility to GO. This effect was comparatively less than that for Pgp and required the inhibition of Pgp for detection in cells that coexpressed both transporters. Because MK-571 and CSA failed to affect cytotoxicity in a portion of Pgp-positive/MRP-positive AML samples, additional resistance mechanisms are likely important.

scholarly journals Clonal evolution of acute myeloid leukemia with FLT3-ITD mutation under treatment with midostaurin

Blood ◽  
2021 ◽  
Author(s):  
Laura Katharina Schmalbrock ◽  
Anna Dolnik ◽  
Sibylle Cocciardi ◽  
Eric Sträng ◽  
Frauke Theis ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Clonal Evolution ◽  
Resistance Mechanisms ◽  
Phase Iii ◽  
Mutational Change ◽  
Paired Samples ◽  
Underlying Mechanisms ◽  
Acute Myeloid

In the international randomized phase III RATIFY trial, the multi-kinase inhibitor midostaurin significantly improved overall and event-free survival in patients 18-59 years of age with FLT3-mutated acute myeloid leukemia (AML). However, only 59% of patients on the midostaurin arm achieved protocol-specified complete remission (CR) and almost half of patients achieving CR relapsed. To explore underlying mechanisms of resistance, we studied patterns of clonal evolution in patients with FLT3-internal tandem duplications (ITD) positive AML who were entered on the RATIFY or the AMLSG 16-10 trial and received treatment with midostaurin. To this end, paired samples from 54 patients obtained at time of diagnosis and at time of either relapsed or refractory disease were analyzed using conventional Genescan-based testing for FLT3-ITD as well as whole exome sequencing. At the time of disease resistance or progression, almost half of the patients (46%) became FLT3-ITD negative, but acquired mutations in signaling pathways (e.g. MAPK), thereby providing a new proliferative advantage. In cases with FLT3-ITD persistence, the selection of resistant ITD-clones was found in 11% as potential drivers of disease. In 32% of cases, no FLT3-ITD mutational change was observed suggesting either resistance mechanisms bypassing FLT3-inhibition or loss of midostaurin inhibitory activity due to inadequate drug levels. In summary, our study provides novel insights into the clonal evolution and resistance mechanisms of FLT3-ITD mutated AML under treatment with midostaurin in combination with intensive chemotherapy.

scholarly journals FLT3 Tyrosine Kinase Inhibitors for the Treatment of Fit and Unfit Patients with FLT3-Mutated AML: A Systematic Review

2021 ◽  
Vol 22 (11) ◽  
pp. 5873
Author(s):  
Michael Loschi ◽  
Rinzine Sammut ◽  
Edmond Chiche ◽  
Thomas Cluzeau
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Current Knowledge ◽  
Complete Response ◽  
Resistance Mechanisms ◽  
Current Lines ◽  
Acute Myeloid

FLT3-mutated acute myeloid leukemia accounts for around 30% of acute myeloid leukemia (AML). The mutation carried a poor prognosis until the rise of tyrosine kinase inhibitors (TKIs). New potent and specific inhibitors have successfully altered the course of the disease, increasing the complete response rate and the survival of patients with FLT3-mutated AML. The aim of this article is to review all the current knowledge on these game-changing drugs as well as the unsolved issues raised by their use for fit and unfit FLT3-mutated AML patients. To this end, we analyzed the results of phase I, II, III clinical trials evaluating FLT3-TKI both in the first-line, relapse monotherapy or in combination referenced in the PubMed, the American Society of Hematology, the European Hematology Association, and the Clinicaltrials.gov databases, as well as basic science reports on TKI resistance from the same databases. The review follows a chronological presentation of the different trials that allowed the development of first- and second-generation TKI and ends with a review of the current lines of evidence on leukemic blasts resistance mechanisms that allow them to escape TKI.

scholarly journals Dual inhibition of FLT3 and AXL by gilteritinib overcomes hematopoietic niche-driven resistance mechanisms in FLT3-ITD acute myeloid leukemia

2021 ◽  
pp. clincanres.3114.2020
Author(s):  
Pierre-Yves Dumas ◽  
Arnaud Villacreces ◽  
Amélie V. Guitart ◽  
El habhab Ali ◽  
Layal Massara ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Resistance Mechanisms ◽  
Dual Inhibition ◽  
Hematopoietic Niche ◽  
Acute Myeloid

JC-1: a very sensitive fluorescent probe to test Pgp activity in adult acute myeloid leukemia

Blood ◽  
2001 ◽  
Vol 97 (2) ◽  
pp. 502-508 ◽  
Author(s):  
Ollivier Legrand ◽  
Jean-Yves Perrot ◽  
Ghislaine Simonin ◽  
Marion Baudard ◽  
Jean-Pierre Marie
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Resistance Mechanisms ◽  
Rhodamine 123 ◽  
Clinical Samples ◽  
Highly Sensitive ◽  
Intermediate Expression ◽  
Acute Myeloid

Abstract One of the best-characterized resistance mechanisms in acute myeloid leukemia (AML) is the drug extrusion mediated by P-glycoprotein (Pgp). Recently the results of workshops organized by several groups concluded that accurate measurement of low activity of Pgp is a difficult goal in clinical samples. Therefore, highly sensitive and specific assays were developed to assess the functionality of Pgp using JC-1, a fluorescent molecule with the different emission wavelength (green and red fluorescence) according to its concentration in 129 AML samples. It was shown that JC-1 (green and red bands) may define 3 groups of patients: resistant (R) (29% of patients), intermediate (I) (36%), and sensitive (S) (35%). In contrast, rhodamine 123 assay detected only the R group defined by JC-1. Nevertheless, the I group has an intermediate expression of Pgp (0.39, 0.29, and 0.19 for the R, I, and S groups, respectively, P = .002), an intermediate biologic profile (percentage of CD34, 95%, 67%, and 44%, respectively, P < .0001; in vitro resistance to daunorubicin, 94 μM, 20 μM, and 12 μM, respectively,P = .02), and an intermediate prognosis (achievement of complete remission, 55%, 65%, and 87%, P = .006; 3-year disease-free survival, 11%, 16%, and 36%, respectively,P = .005; and 3-year overall survival, 0%, 20%, and 51%, respectively, P < .0001). Therefore, JC-1 appeared to be a more convenient and simple way to detect a functional Pgp in clinical AML samples than rhodamine 123.

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