scholarly journals New insight into the catalytic -dependent and -independent roles of METTL3 in sustaining aberrant translation in chronic myeloid leukemia

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Zaira Ianniello ◽  
Melissa Sorci ◽  
Lavinia Ceci Ginistrelli ◽  
Alessia Iaiza ◽  
Marcella Marchioni ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Ribosome Biogenesis ◽  
Kinase Inhibitors ◽  
Myeloproliferative Neoplasm ◽  
Mrna Translation ◽  
Translation Efficiency ◽  
Expression Of Genes ◽  
First Choice

AbstractChronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the presence of tyrosine kinase BCR-ABL1 fusion protein, which deregulate transcription and mRNA translation. Tyrosine kinase inhibitors (TKIs) are the first-choice treatment. However, resistance to TKIs remains a challenge to cure CML patients. Here, we reveal that the m6A methyltransferase complex METTL3/METTL14 is upregulated in CML patients and that is required for proliferation of primary CML cells and CML cell lines sensitive and resistant to the TKI imatinib. We demonstrate that depletion of METTL3 strongly impairs global translation efficiency. In particular, our data show that METTL3 is crucial for the expression of genes involved in ribosome biogenesis and translation. Specifically, we found that METTL3 directly regulates the level of PES1 protein identified as an oncogene in several tumors. We propose a model in which nuclear METTL3/METTL14 methyltransferase complex modified nascent transcripts whose translation is enhanced by cytoplasmic localization of METTL3, independently from its catalytic activity. In conclusion, our results point to METTL3 as a novel relevant oncogene in CML and as a promising therapeutic target for TKI resistant CML.

A Rare Case of Chronic Myeloid Leukemia with t(3;9;22) 3-way Translocation

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S147-S147
Author(s):  
S Elzamly ◽  
O Padilla ◽  
M McAlice ◽  
M Gohar ◽  
S Gaur ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chromosomal Abnormalities ◽  
Fusion Gene ◽  
Myeloproliferative Neoplasm ◽  
Molecular Response ◽  
Hematopoietic Stem

Abstract Introduction/Objective Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm originating from malignant clonal proliferation of a pluripotent hematopoietic stem cell. CML is characterized by a reciprocal translocation between chromosomes 9 and 22, t(9;22)(q34;q11), that gives rise to an abnormal chromosome 22 called the Philadelphia (Ph) chromosome. The translocation results in the formation of a chimeric BCR-ABL1 fusion gene, which is the molecular hallmark of the disease. However, 5-10% of CML patients present with additional chromosomal abnormalities which is often considered a sign of clonal evolution, genetic instability, and is generally thought to portend a poor prognosis. Methods We present a case of CML with a rare 3- way translocation, t(3;9;22)(q21;q34;q11.2), who achieved a major molecular response on imatinib for 18 months. A review of the literature and Mitelman database search is presented focusing on the prognostic implications of this 3 way translocation in the era of tyrosine kinase inhibitors starting in 2001 till now. Results Twenty seven cases were reported, but the patient therapeutic response to imatinib and clinical outcome were only reported in 11 cases. Nine cases achieved a cytogenetic remission while the remaining two cases had an adverse outcome. Conclusion Taken in conjunction with the favorable outcome in our patient, we suggest that t(3;9;22) is not an adverse prognostic factor in the era of tyrosine kinase inhibitors.

scholarly journals Treatment of chronic myeloid leukemia: outcome of the tyrosine kinase inhibitors.

2019 ◽  
pp. 4-9
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Myeloproliferative Neoplasm ◽  
Progression Free Survival ◽  
Molecular Response ◽  
Therapeutic Outcomes ◽  
Reported Data

The chronic myeloid leukemia (CML) is a myeloproliferative neoplasm eligible for targeted therapy with tyrosine kinase inhibitors (TKI). We report in our study the therapeutic outcomes of 173 patients treated for CML in the department of hematology in Aziza Othmana hospital Tunis Tunisia. The front line treatment with Imatinib a first generation TKI has achieved a complete hematological response, a complete cytogenetical response, a major molecular response and a molecular response>4 log in respectively, 95%, 70%, 64% and 40% of patients. The switch to a second generation TKI was indicated in 40% of the patients and has improved the outcomes. The 5-year overall survival (OS) and progression free survival (PFS) were respectively 90 and 91%. Our outcomes are comparable to the reported data and seems to be very encouraging.

scholarly journals Malignancies occurring during therapy with tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) and other hematologic malignancies

Blood ◽  
2011 ◽  
Vol 118 (16) ◽  
pp. 4353-4358 ◽  
Author(s):  
Dushyant Verma ◽  
Hagop Kantarjian ◽  
Sara S. Strom ◽  
Mary Beth Rios ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Myeloproliferative Neoplasm ◽  
Disease Free Survival ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Second Cancers

Abstract Success of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) has given patients hope for a long disease-free-survival. A longer survival raises the question of late effects, including development of another malignancy. Records of 1445 patients with CML/myeloproliferative neoplasm or other hematologic malignancies treated with TKIs were reviewed to investigate frequency and characteristics of second malignancies (other than acute myeloid leukemia, acute lymphocytic leukemia, or myelodysplastic syndrome). The number of second cancers was compared with the number expected from the Surveillance, Epidemiology, and End Results database. After a median follow-up of 107 months (range, 13-362 months) after CML/myeloproliferative neoplasm diagnosis, 66 patients (4.6%) developed 80 second cancers, including skin (31%), prostate (15%), melanoma (13%), digestive system (10%), kidney (4%), thyroid (4%), breast (3%), chronic lymphocytic leukemia (3%), hepatobiliary (3%), and other cancers (14%). Excluding nonmelanoma skin cancers, 55 second cancers were seen in 51 (3.5%) of all patients treated. The risk of second cancer was lower than expected (observed-to-expected ratio, 0.6; 95% confidence interval, 0.44-0.81). Second cancers occur in a small percentage of patients receiving therapy with TKIs for hematologic malignancies, mostly CML. No evidence at the moment suggests that exposure to TKIs increases the risk of developing second cancers.

scholarly journals Compromised anti-tumor–immune features of myeloid cell components in chronic myeloid leukemia patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ibuki Harada ◽  
Haruka Sasaki ◽  
Koichi Murakami ◽  
Akira Nishiyama ◽  
Jun Nakabayashi ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tumor Immunity ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Early Stage ◽  
Myeloproliferative Neoplasm ◽  
Myeloid Cell ◽  
Sequencing Analysis ◽  
Checkpoint Molecule

AbstractChronic myeloid leukemia (CML) is a form of myeloproliferative neoplasm caused by the oncogenic tyrosine kinase BCR-ABL. Although tyrosine kinase inhibitors have dramatically improved the prognosis of patients with CML, several problems such as resistance and recurrence still exist. Immunological control may contribute to solving these problems, and it is important to understand why CML patients fail to spontaneously develop anti-tumor immunity. Here, we show that differentiation of conventional dendritic cells (cDCs), which are vital for anti-tumor immunity, is restricted from an early stage of hematopoiesis in CML. In addition, we found that monocytes and basophils, which are increased in CML patients, express high levels of PD-L1, an immune checkpoint molecule that inhibits T cell responses. Moreover, RNA-sequencing analysis revealed that basophils express genes related to poor prognosis in CML. Our data suggest that BCR-ABL not only disrupts the “accelerator” (i.e., cDCs) but also applies the “brake” (i.e., monocytes and basophils) of anti-tumor immunity, compromising the defense against CML cells.

scholarly journals Imatinib-Induced Tremor in a Patient with Chronic Myeloid Leukemia in Chronic Phase

2019 ◽  
Vol 12 (3) ◽  
pp. 913-917
Author(s):  
Khaldun Obeidat ◽  
Arwa Alsaud ◽  
Amr Ashour ◽  
Bahjat Azrieh ◽  
Mohammad Abu-Tineh ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Myeloproliferative Neoplasm ◽  
Chronic Phase ◽  
Blast Phase ◽  
First And Second Generation

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by three phases: chronic, accelerated, and blast phase. However; first- and second-generation tyrosine kinase inhibitors are used for the treatment of CML with common and uncommon adverse events. Here, we report a 24-year-old male with CML in chronic phase started on imatinib as upfront medication who developed tremor and recovered spontenously after 3 years.

scholarly journals Chronic myeloid leukemia stem cells: targeting therapeutic implications

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hanieh Mojtahedi ◽  
Niloufar Yazdanpanah ◽  
Nima Rezaei
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Myeloproliferative Neoplasm ◽  
Therapy Resistance ◽  
Therapeutic Implications ◽  
Clinical Benefits ◽  
Survival Mechanisms

AbstractChronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm driven by BCR-ABL1 oncoprotein, which plays a pivotal role in CML pathology, diagnosis, and treatment as confirmed by the success of tyrosine kinase inhibitor (TKI) therapy. Despite advances in the development of more potent tyrosine kinase inhibitors, some mechanisms particularly in terms of CML leukemic stem cell (CML LSC) lead to intrinsic or acquired therapy resistance, relapse, and disease progression. In fact, the maintenance CML LSCs in patients who are resistance to TKI therapy indicates the role of CML LSCs in resistance to therapy through survival mechanisms that are not completely dependent on BCR-ABL activity. Targeting therapeutic approaches aim to eradicate CML LSCs through characterization and targeting genetic alteration and molecular pathways involving in CML LSC survival in a favorable leukemic microenvironment and resistance to apoptosis, with the hope of providing a functional cure. In other words, it is possible to develop the combination therapy of TKs with drugs targeting genes or molecules more specifically, which is required for survival mechanisms of CML LSCs, while sparing normal HSCs for clinical benefits along with TKIs.

A REVIEW ON THE ROLE OF TYROSINE KINASE INHIBITORS AVAILABLE FOR THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA

2020 ◽  
Vol 7 (2) ◽  
pp. 205-211
Author(s):  
Kaynat Fatima ◽  
Syed Tasleem Raza ◽  
Ale Eba ◽  
Sanchita Srivastava ◽  
Farzana Mahdi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

The function of protein kinases is to transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are linked to the initiation and development of human cancer. The recent development of small molecule kinase inhibitors for the treatment of different types of cancer in clinical therapy has proven successful. Significantly, after the G-protein-coupled receptors, protein kinases are the second most active category of drug targets. Imatinib mesylate was the first tyrosine kinase inhibitor (TKI), approved for chronic myeloid leukemia (CML) treatment. Imatinib induces appropriate responses in ~60% of patients; with ~20% discontinuing therapy due to sensitivity, and ~20% developing drug resistance. The introduction of newer TKIs such as, nilotinib, dasatinib, bosutinib, and ponatinib has provided patients with multiple options. Such agents are more active, have specific profiles of side effects and are more likely to reach the necessary milestones. First-line treatment decisions must be focused on CML risk, patient preferences and comorbidities. Given the excellent result, half of the patients eventually fail to seek first-line treatment (due to discomfort or resistance), with many of them needing a third or even further therapy lines. In the present review, we will address the role of tyrosine kinase inhibitors in therapy for chronic myeloid leukemia.

scholarly journals Thrombotic microangiopathy in dasatinib-treated patients with chronic myeloid leukemia

2019 ◽  
Vol 4 (1-2) ◽  
pp. 41-45 ◽  
Author(s):  
Takeo Koshida ◽  
Sylvia Wu ◽  
Hitoshi Suzuki ◽  
Rimda Wanchoo ◽  
Vanesa Bijol ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Kinase Inhibitors ◽  
Thrombotic Microangiopathy ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kidney Biopsy ◽  
Kinase Inhibitor ◽  
Target Effect

Dasatinib is the second-generation tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia. Proteinuria has been reported with this agent. We describe two kidney biopsy–proven cases of dasatinib-induced thrombotic microangiopathy that responded to stoppage of dasatinib and using an alternate tyrosine kinase inhibitor. Certain specific tyrosine kinase inhibitors lead to endothelial injury and renal-limited thrombotic microangiopathy. Hematologists and nephrologists need to be familiar with this off-target effect of dasatinib.

Sign in / Sign up

Export Citation Format

Share Document