scholarly journals Pharmacological strategies to overcome treatment resistance in acute myeloid leukemia: increasing leukemic drug exposure by targeting the resistance factor SAMHD1 and the toxicity factor Top2β

2020 ◽  
Vol 16 (1) ◽  
pp. 7-11 ◽  
Author(s):  
Nikolas Herold
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Drug Exposure ◽  
Treatment Resistance ◽  
Resistance Factor ◽  
Toxicity Factor ◽  
Acute Myeloid

Metabolic Reprogramming of Acute Myeloid Leukemia Blasts By Bone Marrow Stroma Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1585-1585
Author(s):  
Dimitrios Mougiakakos ◽  
Regina Jitschin ◽  
Martina Braun ◽  
Andreas Mackensen
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Aerobic Glycolysis ◽  
Treatment Resistance ◽  
Metabolic Phenotype ◽  
Metabolic Shift ◽  
Bone Marrow Stroma ◽  
Marrow Stroma ◽  
Acute Myeloid

Abstract Introduction: Acute myeloid leukemia (AML) represents the most common form of acute leukemia in adults. Despite the enormous efforts during the last decades treatment resistance is still observed at a high rate. Previous studies have shown that bone marrow stroma promotes an increased resilience of AML blasts towards chemotherapeutics. Furthermore, current data suggest that alterations of the malignant cells’ metabolism could represent a strong determinant for the disease’s (including AML) course and/or treatment resistance. In fact, a deregulated metabolism could lead to a reduced sensitivity towards therapy and it remains to be elucidated whether this is a mechanism contributing to the blast-protective effects elicited by the bone marrow stroma. Here, we sought out to characterize the impact of stroma cells on the AML blasts’ metabolism. Methods and Results: The human bone marrow stroma cell-line HS-5 was utilized for establishing the in vitro niche model. We compared in our assays AML cell lines (THP-1, OCI-AML, and KG-1) as well as primary blasts cultured on a HS-5 monolayer or alone. In line with previous observations we could detect an increased proportion of AML cells in the S-phase of the cell cycle upon co-culture with HS-5. When evaluating the cells’ metabolism we observed a shift towards glycolysis despite presence of oxygen, i.e. aerobic glycolysis or the “Warburg”-effect. Basal glycolysis as well as maximal glycolytic capacity upon blocking ATP production in the mitochondrial respiratory chain was increased. Respiration (including basal respiration, coupling efficacy, and maximal respiratory capacity) was not significantly affected. However, mitochondrial biogenesis appeared reduced. Increased glycolysis was accompanied by an increased up-take of fluorescently labeled glucose as well as an increased expression of glucose transporters. The expression of several glycolytic molecules found to be increased upon HS-5 co-culture. Noticeably, cell-to-cell contact was not a pre-requisite for the metabolic shift. Our data was further corroborated by direct observations from AML patients: AML blasts isolated from the bone marrow exhibited an up-regulated glycolysis as compared to their counterparts from the periphery collected at the same time point. Conclusion: Taken together, our data indicates a stromal cell-mediated metabolic shift in AML blasts towards aerobic glycolysis. This metabolic phenotype is linked to an unfavorable prognosis and increased chemo resistance. The underlying molecular pathways remain to be elucidated and could represent a promising target for future interventions. Disclosures No relevant conflicts of interest to declare.

scholarly journals Glucocorticoids enhance the antileukemic activity of FLT3 inhibitors in FLT3-mutant acute myeloid leukemia

Blood ◽  
2020 ◽  
Vol 136 (9) ◽  
pp. 1067-1079 ◽  
Author(s):  
Melat T. Gebru ◽  
Jennifer M. Atkinson ◽  
Megan M. Young ◽  
Lijun Zhang ◽  
Zhenyuan Tang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Drug Exposure ◽  
Residual Disease ◽  
Initial Response ◽  
Antileukemic Activity ◽  
Proapoptotic Protein ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

Abstract FLT3 is a frequently mutated gene that is highly associated with a poor prognosis in acute myeloid leukemia (AML). Despite initially responding to FLT3 inhibitors, most patients eventually relapse with drug resistance. The mechanism by which resistance arises and the initial response to drug treatment that promotes cell survival is unknown. Recent studies show that a transiently maintained subpopulation of drug-sensitive cells, so-called drug-tolerant "persisters" (DTPs), can survive cytotoxic drug exposure despite lacking resistance-conferring mutations. Using RNA sequencing and drug screening, we find that treatment of FLT3 internal tandem duplication AML cells with quizartinib, a selective FLT3 inhibitor, upregulates inflammatory genes in DTPs and thereby confers susceptibility to anti-inflammatory glucocorticoids (GCs). Mechanistically, the combination of FLT3 inhibitors and GCs enhances cell death of FLT3 mutant, but not wild-type, cells through GC-receptor–dependent upregulation of the proapoptotic protein BIM and proteasomal degradation of the antiapoptotic protein MCL-1. Moreover, the enhanced antileukemic activity by quizartinib and dexamethasone combination has been validated using primary AML patient samples and xenograft mouse models. Collectively, our study indicates that the combination of FLT3 inhibitors and GCs has the potential to eliminate DTPs and therefore prevent minimal residual disease, mutational drug resistance, and relapse in FLT3-mutant AML.

Abstract B01: Mechanisms of treatment resistance following Ras targeted therapy in acute myeloid leukemia.

2015 ◽  
Author(s):  
Craig E. Eckfeldt ◽  
Robin DW Lee ◽  
Emily J. Pomeroy ◽  
Alpay N. Temiz ◽  
Susan K. Rathe ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Targeted Therapy ◽  
Myeloid Leukemia ◽  
Treatment Resistance ◽  
Acute Myeloid

scholarly journals Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia

Blood ◽  
2019 ◽  
Vol 133 (1) ◽  
pp. 7-17 ◽  
Author(s):  
Courtney D. DiNardo ◽  
Keith Pratz ◽  
Vinod Pullarkat ◽  
Brian A. Jonas ◽  
Martha Arellano ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Tumor Lysis Syndrome ◽  
Treatment Resistance ◽  
B Cell Lymphoma ◽  
Poor Risk ◽  
Treatment Naïve ◽  
Acute Myeloid

Abstract Older patients with acute myeloid leukemia (AML) respond poorly to standard induction therapy. B-cell lymphoma 2 (BCL-2) overexpression is implicated in survival of AML cells and treatment resistance. We report safety and efficacy of venetoclax with decitabine or azacitidine from a large, multicenter, phase 1b dose-escalation and expansion study. Patients (N = 145) were at least 65 years old with treatment-naive AML and were ineligible for intensive chemotherapy. During dose escalation, oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decitabine (20 mg/m2, days 1-5, intravenously [IV]) or azacitidine (75 mg/m2, days 1-7, IV or subcutaneously). In the expansion, 400 or 800 mg venetoclax with either hypomethylating agent (HMA) was given. Median age was 74 years, with poor-risk cytogenetics in 49% of patients. Common adverse events (>30%) included nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count. No tumor lysis syndrome was observed. With a median time on study of 8.9 months, 67% of patients (all doses) achieved complete remission (CR) + CR with incomplete count recovery (CRi), with a CR + CRi rate of 73% in the venetoclax 400 mg + HMA cohort. Patients with poor-risk cytogenetics and those at least 75 years old had CR + CRi rates of 60% and 65%, respectively. The median duration of CR + CRi (all patients) was 11.3 months, and median overall survival (mOS) was 17.5 months; mOS has not been reached for the 400-mg venetoclax cohort. The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML (This trial was registered at www.clinicaltrials.gov as #NCT02203773).

scholarly journals Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Kiyomi Morita ◽  
Feng Wang ◽  
Katharina Jahn ◽  
Tianyuan Hu ◽  
Tomoyuki Tanaka ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Single Cell ◽  
Myeloid Leukemia ◽  
Single Cell Analysis ◽  
Clonal Evolution ◽  
Evolutionary Process ◽  
Treatment Resistance ◽  
Clonal Diversity ◽  
Clonal Architecture ◽  
Acute Myeloid

AbstractClonal diversity is a consequence of cancer cell evolution driven by Darwinian selection. Precise characterization of clonal architecture is essential to understand the evolutionary history of tumor development and its association with treatment resistance. Here, using a single-cell DNA sequencing, we report the clonal architecture and mutational histories of 123 acute myeloid leukemia (AML) patients. The single-cell data reveals cell-level mutation co-occurrence and enables reconstruction of mutational histories characterized by linear and branching patterns of clonal evolution, with the latter including convergent evolution. Through xenotransplantion, we show leukemia initiating capabilities of individual subclones evolving in parallel. Also, by simultaneous single-cell DNA and cell surface protein analysis, we illustrate both genetic and phenotypic evolution in AML. Lastly, single-cell analysis of longitudinal samples reveals underlying evolutionary process of therapeutic resistance. Together, these data unravel clonal diversity and evolution patterns of AML, and highlight their clinical relevance in the era of precision medicine.

scholarly journals miR-451a abrogates treatment resistance in FLT3-ITD-positive acute myeloid leukemia

2018 ◽  
Vol 8 (3) ◽  
Author(s):  
Rosanna H. E. Krakowsky ◽  
Alexander A. Wurm ◽  
Dennis Gerloff ◽  
Christiane Katzerke ◽  
Daniela Bräuer-Hartmann ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Treatment Resistance ◽  
Acute Myeloid

scholarly journals Clonal Evolution of Acute Myeloid Leukemia Revealed by High-Throughput Single-Cell Genomics

2020 ◽  
Author(s):  
Kiyomi Morita ◽  
Feng Wang ◽  
Katharina Jahn ◽  
Jack Kuipers ◽  
Yuanqing Yan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dna Sequencing ◽  
Single Cell ◽  
High Throughput ◽  
Myeloid Leukemia ◽  
Clonal Evolution ◽  
Treatment Resistance ◽  
Clonal Diversity ◽  
History Of ◽  
Acute Myeloid

SummaryOne of the pervasive features of cancer is the diversity of mutations found in malignant cells within the same tumor; a phenomenon called clonal diversity or intratumor heterogeneity. Clonal diversity allows tumors to adapt to the selective pressure of treatment and likely contributes to the development of treatment resistance and cancer recurrence. Thus, the ability to precisely delineate the clonal substructure of a tumor, including the evolutionary history of its development and the co-occurrence of its mutations, is necessary to understand and overcome treatment resistance. However, DNA sequencing of bulk tumor samples cannot accurately resolve complex clonal architectures. Here, we performed high-throughput single-cell DNA sequencing to quantitatively assess the clonal architecture of acute myeloid leukemia (AML). We sequenced a total of 556,951 cells from 77 patients with AML for 19 genes known to be recurrently mutated in AML. The data revealed clonal relationship among AML driver mutations and identified mutations that often co-occurred (e.g., NPM1/FLT3-ITD, DNMT3A/NPM1, SRSF2/IDH2, and WT1/FLT3-ITD) and those that were mutually exclusive (e.g., NRAS/KRAS, FLT3-D835/ITD, and IDH1/IDH2) at single-cell resolution. Reconstruction of the tumor phylogeny uncovered history of tumor development that is characterized by linear and branching clonal evolution patterns with latter involving functional convergence of separately evolved clones. Analysis of longitudinal samples revealed remodeling of clonal architecture in response to therapeutic pressure that is driven by clonal selection. Furthermore, in this AML cohort, higher clonal diversity (≥4 subclones) was associated with significantly worse overall survival. These data portray clonal relationship, architecture, and evolution of AML driver genes with unprecedented resolution, and illuminate the role of clonal diversity in therapeutic resistance, relapse and clinical outcome in AML.

scholarly journals A phase 1/2 study of the oral FLT3 inhibitor pexidartinib in relapsed/refractory FLT3-ITD–mutant acute myeloid leukemia

2020 ◽  
Vol 4 (8) ◽  
pp. 1711-1721 ◽  
Author(s):  
Catherine C. Smith ◽  
Mark J. Levis ◽  
Olga Frankfurt ◽  
John M. Pagel ◽  
Gail J. Roboz ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Drug Exposure ◽  
Kinase Inhibitors ◽  
Response Rate ◽  
Phase 1 ◽  
Complete Response ◽  
Flt3 Inhibitor ◽  
Acute Myeloid

Abstract FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitors (TKIs) have activity in acute myeloid leukemia (AML) patients with FLT3 internal tandem duplication (ITD) mutations, but efficacy is limited by resistance-conferring kinase domain mutations. This phase 1/2 study evaluated the safety, tolerability, and efficacy of the oral FLT3 inhibitor PLX3397 (pexidartinib), which has activity against the FLT3 TKI–resistant F691L gatekeeper mutation in relapsed/refractory FLT3-ITD–mutant AML. Ninety patients were treated: 34 in dose escalation (part 1) and 56 in dose expansion (part 2). Doses of 800 to 5000 mg per day in divided doses were tested. No maximally tolerated dose was reached. Plasma inhibitory assay demonstrated that patients dosed with ≥3000 mg had sufficient levels of active drug in their trough plasma samples to achieve 95% inhibition of FLT3 phosphorylation in an FLT3-ITD AML cell line. Based on a plateau in drug exposure, the 3000-mg dose was chosen as the recommended phase 2 dose. The most frequently reported treatment-emergent adverse events were diarrhea (50%), fatigue (47%), and nausea (46%). Based on modified response criteria, the overall response rate to pexidartinib among all patients was 21%. Twenty-three percent of patients treated at ≥2000 mg responded. The overall composite complete response rate for the study was 11%. Six patients were successfully bridged to transplantation. Median overall survival (OS) of patients treated in dose expansion was 112 days (90% confidence interval [CI], 77-150 days), and median OS of responders with complete remission with or without recovery of blood counts was 265 days (90% CI, 170-422 days). This trial was registered at www.clinicaltrials.gov as #NCT01349049.

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