scholarly journals Co-expression of the CBFβ-MYH11 and BCR-ABL fusion genes in chronic myeloid leukaemia / Coexistenţa genelor de fuziune CBFβ-MYH11 şi BCR-ABL în leucemia mieloidă cronică

2015 ◽  
Vol 23 (2) ◽  
Author(s):  
Roxana Popescu ◽  
Angela Dăscălescu ◽  
Cătălin Dănăilă ◽  
Doramina Ghiorghiu ◽  
Mihaela Zlei ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Philadelphia Chromosome ◽  
Tyrosine Kinase Domain ◽  
Blast Transformation ◽  
Monocytic Differentiation ◽  
Blast Phase ◽  
Therapeutic Decisions

AbstractThe coexistence of t(9;22) and inv(16) has been described in a very limited number of cases of CML, de novo or therapy-related AML. We report a patient with CML who presented both inversion of chromosome 16 and Philadelphia chromosome and evolved towards the blast phase under treatment with Imatinib. Laboratory diagnosis and monitoring was made by flow cytometry, conventional cytogenetics and molecular genetics techniques. The inv(16), detected by karyotyping in the Philadelphia chromosome positive clone at the moment of the blast transformation, was retrospectively assessed by means of real-time PCR, and was proved to have been present since diagnosis. The bone marrow biopsy performed in the blast phase of CML confirmed the presence of blasts belonging to the myeloid lineage, with indications of monocytic differentiation, frequently associated with inv(16). Moreover, the case also associated a F359V tyrosine kinase domain mutation, resulting in intermediate resistance to Imatinib and Nilotinib, which imposed therapy-switch to Dasatinib. In our case the evolution was progressive, followed by death due to lack of response to tyrosine kinase inhibitors, 18 months after diagnosis. The coexistence of t(9;22) and inv(16) in CML seems to be associated with an aggressive clinical evolution and resistance to tyrosine kinase inhibitor therapy. Due to the very small number of cases described in literature, therapeutic decisions are still difficult for patients displaying these abnormalities

Outcome after Frontline Therapy with the Hyper-CVAD and Imatinib Mesylate Regimen for Adults with De Novo or Minimally Treated Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2931-2931 ◽  
Author(s):  
Deborah A. Thomas ◽  
Hagop M Kantarjian ◽  
Jorge Cortes ◽  
Farhad Ravandi ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Imatinib Mesylate ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Early Death ◽  
Cell Transplant ◽  
Active Disease

Abstract Historically, complete remission (CR) rates with hyper-CVAD (cyclophosphamide, vincristine [VCR], doxorubicin and dexamethasone alternating with methotrexate and cytarabine) in de novo adult Ph-ALL were 90% or better; disease recurrence remained problematic. The selective ABL tyrosine kinase inhibitor (TKI) imatinib mesylate was thus incorporated into the hyper-CVAD regimen for de novo or minimally treated Ph-ALL [Thomas, Blood 103:4396, 2004]. The final regimen included imatinib 600 mg days 1–14 of induction, 600 mg continuously with courses 2–8, followed by escalation to 800 mg as tolerated during 24 mos of maintenance therapy with monthly VCR and prednisone interrupted by 2 intensifications with hyper-CVAD and imatinib, then imatinib indefinitely. Allogeneic stem cell transplant (SCT) was performed in first CR as feasible. The study accrued from April 2001 to September 2006. Fifty-four pts with imatinib-naive de novo or minimally treated Ph-ALL were treated. Forty-five pts had active disease, untreated (n=39) or refractory (n=6) to one induction course; 9 were in CR at start. Median age was 51 yrs (range, 17–84); 52% were male, and 13% had CNS disease at presentation. Of the 45 pts with active disease, 42 (93%) achieved CR (1 CRp, 1 partial response, 1 early death from sepsis). All 6 refractory patients achieved CR. Molecular CR rate (MCR, confirmed by nested PCR) prior to SCT was 52% overall. Sixteen pts (33%) underwent allogeneic SCT in first CR within a median of 5 mos from start of therapy (range 1–13). In the de novo group, 14 pts with median age of 37 yrs underwent allogeneic SCT in first CR whereas 33 pts with a median age of 53 years did not. The 3-yr survival (OS) rates were 66% vs 49% with or without SCT, respectively, p=0.36. The 3-yr CR duration rate was 84% for pts who achieved MCR (2 of 16 had SCT) compared to 64% for those who did not (14 of 35 had SCT), p=0.1; OS rates were similar regardless of MCR status. With a median follow-up of 52 mos (range 19–83+), 22% pts relapsed within a median of 15 mos from the start of therapy (range 8–42), including 2 after allogeneic SCT without imatinib maintenance. Detection of additional chromosome abnormalities at presentation did not influence outcome. In the de novo group, 4 of 9 evaluable relapses had ABL kinase domain mutations [E459K, Y253H, Y253F, F359V], none harbored T315I. The addition of imatinib improved outcome compared with hyper-CVAD alone (irrespective of allogeneic SCT); overall 3-yr CR duration and OS rates were 68% vs 25% and 55% vs 15%, respectively, p<0.001. Incorporation of second or later generation tyrosine kinase inhibitors into the hyper-CVAD regimen may further improve on the favorable imatinib experience. Allogeneic SCT in the TKI era needs to be reexamined in a prospective randomized trial.

scholarly journals Receptor tyrosine kinase signaling required for integrin alpha v beta 5-directed cell motility but not adhesion on vitronectin.

1994 ◽  
Vol 127 (3) ◽  
pp. 859-866 ◽  
Author(s):  
R L Klemke ◽  
M Yebra ◽  
E M Bayna ◽  
D A Cheresh
Keyword(s):  
Cell Migration ◽  
Tyrosine Kinase ◽  
Cell Motility ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Growth Factor Receptor ◽  
Dependent Manner ◽  
Pkc Activation

FG human pancreatic carcinoma cells adhere to vitronectin using integrin alpha v beta 5 yet are unable to migrate on this ligand whereas they readily migrate on collagen in an alpha 2 beta 1-dependent manner. We report here that epidermal growth factor receptor (EGFR) activation leads to de novo alpha v beta 5-dependent FG cell migration on vitronectin. The EGFR specific tyrosine kinase inhibitor tyrphostin 25 selectively prevents EGFR autophosphorylation thereby preventing the EGF-induced FG cell migration response on vitronectin without affecting constitutive migration on collagen. Protein kinase C (PKC) activation also leads to alpha v beta 5-directed motility on vitronectin; however, this is not blocked by tyrosine kinase inhibitors. In this case, PKC activation appears to be associated with and downstream of EGFR signaling since calphostin C, an inhibitor of PKC, blocks FG cell migration on vitronectin induced by either PKC or EGF. These findings represent the first report implicating a receptor tyrosine kinase in a specific integrin mediated cell motility event independent of adhesion.

scholarly journals Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4820
Author(s):  
Raquel Alves ◽  
Ana Cristina Gonçalves ◽  
Sergio Rutella ◽  
António M. Almeida ◽  
Javier De Las De Las Rivas ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Fusion Gene ◽  
Computational Prediction ◽  
Tki Resistance

Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.

HHGV678, a Novel Tyrosine Kinase Inhibitor, Inhibits the Cell Growth of Imatinib-Sensitive and Resistant BCR-ABL Positive Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4240-4240
Author(s):  
Lin Qiu ◽  
Xiao-dan Wang ◽  
Fang Ge ◽  
Xiu-li Wang ◽  
Bo-long Zhang ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tyrosine Kinase ◽  
Growth Inhibition ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Blast Crisis ◽  
Point Mutations ◽  
Tyrosine Kinase Domain ◽  
Significant Activity

Abstract Imatinib (IM) is a higherly effective targeted drug for CML. However, some CML patients, especially accelerated and blast crisis phase, often relapse due to drug resistance resulting from the emergence of IM-resistant point mutations within the BCR-ABL tyrosine kinase domain. This stimulates the development of new kinase inhibitors that are able to override resistance to IM. HHGV678 is a novel tyrosine kinase inhibitor and we employed IM-sensitive (K562 and 32Dp210) and resistant (K562R and fifteen 32Dp210 mutants) BCR-ABL+ cell lines to compare HHGV678 with IM on growth inhibition. In addition, synergistic effect of HHGV678 with IM was observed in 32Dp210 and 5 BCR-ABL mutants frequently observed in CML patients. MTT assay results showed that the estimated IC50 value of HHGV678 for K562 and 32Dp210 were 15.5 and 28-fold, for K562R and 15 BCR-ABL mutants, were 1.4–124.0-fold lower than that of IM, indicating that HHGV678 was a more effective than IM against cell growth of IM-sensitive and resistant cells. Using combination index analysis, HHGV678 displayed synergistic growth inhibition when used with IM in BCR-ABL mutants (M244V, Q252H, Y253H, E255K and T315I). HHGV678, combined with IM at their IC50 concentration induced apoptosis 2–5 fold higher than that of HHGV678 alone in BCR-ABL mutants respectively, by annexin-V staining. At the same condition, HHGV6787 resulted in remarkable decrease in CrKL phosphorylation as determined by western blot. We conclude that HHGV678 have significant activity against IM-sensitive and resistant BCR-ABL+ cell, especially when it combined with IM that warrant further investigation in clinical trials.

scholarly journals Therapeutic Vulnerabilities in FLT3-Mutant AML Unmasked by Palbociclib

2018 ◽  
Vol 19 (12) ◽  
pp. 3987 ◽  
Author(s):  
Iris Uras ◽  
Barbara Maurer ◽  
Sofie Nebenfuehr ◽  
Markus Zojer ◽  
Peter Valent ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
De Novo ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Single Agent ◽  
Xenograft Model ◽  
Tumor Formation ◽  
Tyrosine Kinase Domain ◽  
Common Denominator

While significant progress has been made in the treatment of acute myeloid leukemia (AML), not all patients can be cured. Mutated in about 1/3 of de novo AML, the FLT3 receptor tyrosine kinase is an attractive target for drug development, activating mutations of the FLT3 map to the juxtamembrane domain (internal tandem duplications, ITD) or the tyrosine kinase domain (TKD), most frequently at codon D835. While small molecule tyrosine kinase inhibitors (TKI) effectively target ITD mutant forms, those on the TKD are not responsive. Moreover, FLT3 inhibition fails to induce a persistent response in patients due to mutational resistance. More potent compounds with broader inhibitory effects on multiple FLT3 mutations are highly desirable. We describe a critical role of CDK6 in the survival of FLT3+ AML cells as palbociclib induced apoptosis not only in FLT3–ITD+ cells but also in FLT3–D835Y+ cells. Antineoplastic effects were also seen in primary patient-derived cells and in a xenograft model, where therapy effectively suppressed tumor formation in vivo at clinically relevant concentrations. In cells with FLT3–ITD or -TKD mutations, the CDK6 protein not only affects cell cycle progression but also transcriptionally regulates oncogenic kinases mediating intrinsic drug resistance, including AURORA and AKT—a feature not shared by its homolog CDK4. While AKT and AURORA kinase inhibitors have significant therapeutic potential in AML, single agent activity has not been proven overly effective. We describe synergistic combination effects when applying these drugs together with palbociclib which could be readily translated to patients with AML bearing FLT3–ITD or –TKD mutations. Targeting synergistically acting vulnerabilities, with CDK6 being the common denominator, may represent a promising strategy to improve AML patient responses and to reduce the incidence of selection of resistance-inducing mutations.

scholarly journals The Interface between BCR-ABL-Dependent and -Independent Resistance Signaling Pathways in Chronic Myeloid Leukemia

2012 ◽  
Vol 2012 ◽  
pp. 1-19 ◽  
Author(s):  
Gabriela Nestal de Moraes ◽  
Paloma Silva Souza ◽  
Fernanda Casal de Faria Costas ◽  
Flavia Cunha Vasconcelos ◽  
Flaviana Ruade Souza Reis ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Resistance Mechanisms ◽  
Imatinib Resistance ◽  
Abl Tyrosine Kinase ◽  
Alternative Drug

Chronic myeloid leukemia (CML) is a clonal hematopoietic disorder characterized by the presence of the Philadelphia chromosome which resulted from the reciprocal translocation between chromosomes 9 and 22. The pathogenesis of CML involves the constitutive activation of the BCR-ABL tyrosine kinase, which governs malignant disease by activating multiple signal transduction pathways. The BCR-ABL kinase inhibitor, imatinib, is the front-line treatment for CML, but the emergence of imatinib resistance and other tyrosine kinase inhibitors (TKIs) has called attention for additional resistance mechanisms and has led to the search for alternative drug treatments. In this paper, we discuss our current understanding of mechanisms, related or unrelated to BCR-ABL, which have been shown to account for chemoresistance and treatment failure. We focus on the potential role of the influx and efflux transporters, the inhibitor of apoptosis proteins, and transcription factor-mediated signals as feasible molecular targets to overcome the development of TKIs resistance in CML.

Emerging BCR/ABL1 Mutations Under Treatment with Tyrosine Kinase Inhibitors in Paediatric Acute Lymphoblastic Leukaemia

2015 ◽  
Vol 134 (2) ◽  
pp. 71-75 ◽  
Author(s):  
Agueda Molinos-Quintana ◽  
Virginia Aquino ◽  
Isabel Montero ◽  
Concepción Pérez-de Soto ◽  
Raúl García-Lozano ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Clonal Selection ◽  
Philadelphia Chromosome ◽  
Kinase Domain ◽  
Mutational Status ◽  
Tyrosine Kinase Inhibitor Therapy

We report on the emergence and clinical relevance of an unusual BCR-ABL1 kinase domain mutational status in a 2-year-old female with p210-BCR-ABL Philadelphia chromosome-positive acute lymphoblastic leukaemia. We detected three BCR-ABL1 clones determined by the presence of the E255V, D276G and F317L mutations. We point out the usefulness of searching for mutated populations that survive tyrosine-kinase inhibitor therapy and the role of their clonal selection over time in relation to therapeutic intervention.

Monitoring efforts in myeloproliferative neoplasms

2020 ◽  
pp. 234-248
Author(s):  
Daniel Egan ◽  
Jerald P. Radich
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Polycythaemia Vera ◽  
Mrna Levels ◽  
Tyrosine Kinase Inhibitor Therapy

Targeted therapy with tyrosine kinase inhibitors (TKI) has transformed the therapy of chronic myeloid leukaemia (CML), and is increasingly playing a role in the management of the myeloproliferative neoplasms (MPN), as a whole. In CML, the Philadelphia chromosome drives disease pathogenesis, and is the basis of both therapy (aimed at the BCR-ABL protein) and monitoring (the BCR-ABL chimeric mRNA). The efficacy of tyrosine kinase inhibitor therapy in CML is now accessed by reaching treatment milestones based on the BCR-ABL mRNA levels. In MPN, the landscape of genetic mutations associated with essential thrombocytosis (ET), polycythaemia vera (PV), and primary myelofibrosis (PMF) is ongoing. However, the recent discoveries of the JAK2 V617F and calreticulin mutations (for example) have a similar potential for disease targeting and monitoring as in CML.

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