scholarly journals Stromal CYR61 Confers Resistance to Mitoxantrone via Spleen Tyrosine Kinase Activation in Human Acute Myeloid Leukaemia

2015 ◽  
Vol 170 (5) ◽  
pp. 704-718 ◽  
Author(s):  
Xin Long ◽  
Yang Yu ◽  
Laszlo Perlaky ◽  
Tsz-Kwong Man ◽  
Michele S. Redell
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukaemia ◽  
Spleen Tyrosine Kinase ◽  
Kinase Activation ◽  
Acute Myeloid

scholarly journals Whole Exome Sequencing of FLT3-ITD Sorafenib-Resistant Acute Myeloid Leukaemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1400-1400 ◽  
Author(s):  
Stephen Sze Yuen Lam ◽  
Chae Yin Cher ◽  
Nelson K. L. Ng ◽  
Cheuk Him Man ◽  
Anskar Y.H. Leung
Keyword(s):  
Drug Resistance ◽  
Acute Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukaemia ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Drug Resistant ◽  
Single Nucleotide ◽  
Whole Exome ◽  
Acute Myeloid

Abstract Acute myeloid leukaemia (AML) is a heterogeneous disease characterised by an abnormal increase in myeloblasts. Current treatment protocol employs the standard "7+3" chemotherapy regimen complemented with haematopoietic stem cell transplantation. However overall cure rate remains at 30-40%. Targeted therapy, especially the use of tyrosine kinase inhibitors, has been the main focus in the pursuit of an alternative solution. Internal tandem duplication at the juxatmembrane domain of fms-like tyrosine kinase 3 (FLT3-ITD) was found in around 30% of AML cases, conferring unfavourable treatment outcome and prognosis. Sorafenib, and other FLT3 inhibitors, successfully induced remission or partial remission in most of the relapsed/refractory FLT3-ITD AML patients (CR/CRi/nCR = 82.4%, n=34 in our sorafenib monotherapy cohort). Although consolidation with combination of sorafenib and chemotherapy or hypomethylating agents was reported to significantly extend the remission period, all patients relapsed with drug resistance. Mutations at the tyrosine kinase domain (TKD) were reported to alter the binding affinity of the drugs to the receptor and hence generate resistance. However, they were found only in around 25% of the patients while other non-mutational mechanisms of resistance have also been reported. Their relative importance in patients remains uncertain. We hypothesised that there is an emergence of drug-resistant clones acquiring new mutations or pathways to develop the resistance. We have performed whole exome sequencing (HiSeq pair-end sequencing of 101 bp) for sorafenib-sensitive and sorafenib-resistant samples obtained from 8 FLT3-ITD relapsed/refractory AML patients before sorafenib treatment and at relapse with drug resistance. Genomic content of the bulk population was observed to change drastically among the 8 patients, with disappearance of single nucleotide polymorphisms (SNPs) and emergence of new SNPs, suggesting the emergence of drug-resistant clones. Emergence of TKD D835Y mutation was observed in 3 patients with variant allele frequencies (VAF) at 11%, 44% and 50% that were undetectable in the sorafenib-sensitive samples. Mutations at other reported sites of TKD were not found. Filtering of the generated list of single nucleotide changes and insertion/deletions (indels) to sort out emerging non-synonymous mutations with high VAF at resistant samples but undetectable in the sensitive samples was done. They include SLC15A1, CDC27, NADKD1, DGAT2, UBXN11, TFR2 and TTBK1, potentially implicated in sorafenib resistance. They are involved in different pathways, including membrane transporter, cell cycle regulation and energy metabolism. Further functional validation of their role in sorafenib resistance is required to understand the mechanisms involved. Disclosures No relevant conflicts of interest to declare.

scholarly journals FLT3 Inhibition in Acute Myeloid Leukaemia – Current Knowledge and Future Prospects

2020 ◽  
Vol 20 (7) ◽  
pp. 513-531 ◽  
Author(s):  
Francesca L. Hogan ◽  
Victoria Williams ◽  
Steven Knapper
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Current Knowledge ◽  
Clinical Development ◽  
Clinical Prognosis ◽  
Acquired Drug Resistance ◽  
Acute Myeloid

Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in 30% of acute myeloid leukaemia (AML) patients at diagnosis and confer an adverse clinical prognosis. Mutated FLT3 has emerged as a viable therapeutic target and a number of FLT3-directed tyrosine kinase inhibitors have progressed through clinical development over the last 10-15 years. The last two years have seen United States Food and Drug Administration (US FDA) approvals of the multi-kinase inhibitor midostaurin for newly-diagnosed FLT3-mutated patients, when used in combination with intensive chemotherapy, and of the more FLT3-selective agent gilteritinib, used as monotherapy, for patients with relapsed or treatment-refractory FLT3-mutated AML. The ‘second generation’ agents, quizartinib and crenolanib, are also at advanced stages of clinical development. Significant challenges remain in negotiating a variety of potential acquired drug resistance mechanisms and in optimizing sequencing of FLT3 inhibitory drugs with existing and novel treatment approaches in different clinical settings, including frontline therapy, relapsed/refractory disease, and maintenance treatment. In this review, the biology of FLT3, the clinical challenge posed by FLT3-mutated AML, the developmental history of the key FLT3-inhibitory compounds, mechanisms of disease resistance, and the future outlook for this group of agents, including current and planned clinical trials, is discussed.

scholarly journals Targeting the FLT3 Mutation in Acute Myeloid Leukaemia

2017 ◽  
Vol 13 (02) ◽  
pp. 139 ◽  
Author(s):  
Sabine Kayser ◽  
Richard F Schlenk ◽  
◽  
◽  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitors ◽  
Point Mutations ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Acute Myeloid

Acute myeloid leukaemia (AML) exhibiting an internal tandem duplication of the FLT3 gene (FLT3-ITD) is an aggressive haematologic malignancy with a poor prognosis due to a high relapse rate and very limited options after relapse with conventional salvage regimens, whereas the prognostic impact of point mutations in the tyrosine kinase domain of the FLT3 gene (FLT3-TKD) are less clear. A number of tyrosine kinase inhibitors (TKIs) have been developed that inhibit the constitutively activated kinase activity caused by the FLT3 mutation, thus interrupting signalling pathways. Early clinical trials of these agents as monotherapy failed to elicit enduring complete responses, leading to clinical testing of FLT3 TKI in combination with conventional chemotherapy. Midostaurin has demonstrated improved survival in combination with standard intensive chemotherapy as compared to standard chemotherapy alone in younger adult patients with newly diagnosed FLT3-mutated AML and is the first and currently the only approved FLT3 TKI. Newer, more selective compounds, such as gilteritinib and crenolanib, have also demonstrated significant potency and specificity. Several combination trials are ongoing or planned in both relapsed and newly diagnosed AML patients with activating FLT3 mutations.

Absence of Bruton's tyrosine kinase (Btk) mutations in patients with acute myeloid leukaemia

1998 ◽  
Vol 102 (5) ◽  
pp. 1241-1248 ◽  
Author(s):  
Konstantinos Ritis ◽  
Matthaios Speletas ◽  
Victoria Tsironidou ◽  
Evaggelia Pardali ◽  
Maria Kanariou ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukaemia ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Acute Myeloid

3002 – REPROGRAMMING OF SERINE METABOLISM IS A METABOLIC VULNERABILITY IN FMS-LIKE TYROSINE KINASE 3 (FLT3) MUTANT ACUTE MYELOID LEUKAEMIA

2020 ◽  
Vol 88 ◽  
pp. S37-S38
Author(s):  
Stefan Bjelosevic ◽  
Emily Gruber ◽  
Andrea Newbold ◽  
Carolyn Shembrey ◽  
Thomas Abrehart ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukaemia ◽  
Serine Metabolism ◽  
Acute Myeloid

scholarly journals The incidence and prognostic effect of Fms-like tyrosine kinase 3 gene internal tandem and nucleolar phosphoprotein 1 genes in acute myeloid leukaemia

Medicine ◽  
2020 ◽  
Vol 99 (51) ◽  
pp. e23707
Author(s):  
Heping Liu ◽  
Xiaolian Zhang ◽  
Ming Li ◽  
Wei Zhou ◽  
Guangrong Jiang ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukaemia ◽  
Prognostic Effect ◽  
Acute Myeloid

Tyrosine kinase inhibitor insensitivity of non-cycling CD34+ human acute myeloid leukaemia cells with FMS-like tyrosine kinase 3 mutations

2011 ◽  
Vol 154 (4) ◽  
pp. 457-465 ◽  
Author(s):  
Caroline L. Alvares ◽  
Tino Schenk ◽  
Sanna Hulkki ◽  
Toon Min ◽  
Gowri Vijayaraghavan ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitor ◽  
Acute Myeloid
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