scholarly journals INNO-406 inhibit the growth of chronic myeloid leukemia and promote its apoptosis via targeting PTEN

2020 ◽  
Author(s):  
Jiandong Sun ◽  
Yilin Wang ◽  
Lirong Sun
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Molecular Mechanism ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Myeloproliferative Neoplasm ◽  
Lyn Kinase ◽  
Apoptotic Protein ◽  
Induced Apoptosis ◽  
Kinase Inhibitory Activity

Abstract Background Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm. INNO-406 is a novel tyrosine kinase inhibitor (TKI) that possess specific Lyn kinase inhibitory activity with no or limited activity against other sarcoma (Src) family member kinases. The present study aimed to confirm the anti-tumor effect of INNO-406 on CML cells, and elucidate the molecular mechanism underlying its effect. Methods The cell proliferation and apoptosis were detected by MTT, western blot and flow cytometry respectively. Results As suggested by the findings, INNO-406 significantly inhibited the proliferation and induced apoptosis of CML cells. In addition, INNO-406 promoted the expression level of PETN. Rescue experiment revealed that PTEN knockdown reversed the effect of INNO-406 which indicated the correlation between INNO-406 and PTEN. Further study determined that PTEN inhibited the phosphorylation of AKT and 4EBP1 and subsequently altered the expression of apoptotic protein expressions including bax, cytochrome c (cyto-c), cleaved caspase3 and bcl-2. In vivo study further confirmed that INNO-406 inhibited the growth of CML cells in vivo by targeting PTEN. Conclusion Based on the above findings, this work extended our understanding of INNO-406 in the chemotherapy of CML and its molecular mechanism.

scholarly journals Therapeutic inhibition of FcγRIIb signaling targets leukemic stem cells in chronic myeloid leukemia

Leukemia ◽  
2020 ◽  
Vol 34 (10) ◽  
pp. 2635-2647
Author(s):  
Oliver Parting ◽  
Samantha Langer ◽  
Maja Kim Kuepper ◽  
Caroline Wessling ◽  
Shaoguang Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Chronic Myeloid Leukemia ◽  
Therapeutic Approach ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Leukemic Stem Cells ◽  
Downstream Signaling ◽  
Targeted Inhibition ◽  
Treatment Free Remission

Abstract Despite the successes achieved with molecular targeted inhibition of the oncogenic driver Bcr-Abl in chronic myeloid leukemia (CML), the majority of patients still require lifelong tyrosine kinase inhibitor (TKI) therapy. This is primarily caused by resisting leukemic stem cells (LSCs), which prevent achievement of treatment-free remission in all patients. Here we describe the ITIM (immunoreceptor tyrosine-based inhibition motif)-containing Fc gamma receptor IIb (FcγRIIb, CD32b) for being critical in LSC resistance and show that targeting FcγRIIb downstream signaling, by using a Food and Drug Administration-approved BTK inhibitor, provides a successful therapeutic approach. First, we identified FcγRIIb upregulation in primary CML stem cells. FcγRIIb depletion caused reduced serial re-plaiting efficiency and cell proliferation in malignant cells. FcγRIIb targeting in both a transgenic and retroviral CML mouse model provided in vivo evidence for successful LSC reduction. Subsequently, we identified BTK as a main downstream mediator and targeting the Bcr-Abl-FcγRIIb-BTK axis in primary CML CD34+ cells using ibrutinib, in combination with standard TKI therapy, significantly increased apoptosis in quiescent CML stem cells thereby contributing to the eradication of LSCs.. As a potential curative therapeutic approach, we therefore suggest combining Bcr-Abl TKI therapy along with BTK inhibition.

scholarly journals Modeling of Chronic Myeloid Leukemia: An Overview ofIn VivoMurine and Human Xenograft Models

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Pallavi Sontakke ◽  
Jenny Jaques ◽  
Edo Vellenga ◽  
Jan Jacob Schuringa
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Therapeutic Approaches ◽  
Retroviral Transduction ◽  
Murine Bone Marrow ◽  
Tki Resistance ◽  
Xenograft Models ◽  
Human Xenograft Models

Over the past years, a wide variety ofin vivomouse models have been generated in order to unravel the molecular pathology of Chronic Myeloid Leukemia (CML) and to develop and improve therapeutic approaches. These models range from (conditional) transgenic models, knock-in models, and murine bone marrow retroviral transduction models followed by transplantation. With the advancement of immunodeficient xenograft models, it has become possible to use human stem/progenitor cells forin vivostudies as well as cells directly derived from CML patients. These models not only mimic CML but also have been instrumental in uncovering various fundamental mechanisms of CML disease progression and tyrosine kinase inhibitor (TKI) resistance. With the availability of iPSC technology, it has become feasible to derive, maintain, and expand CML subclones that are at least genetically identical to those in patients. The following review provides an overview of all murine as well as human xenograft models for CML established till date.

scholarly journals Dasatinib-induced hemorrhagic colitis complicated with cytomegalovirus infection

2017 ◽  
Vol 9 (4) ◽  
Author(s):  
Aya Nakaya ◽  
Yoshiko Azuma ◽  
Shinya Fujita ◽  
Atsushi Satake ◽  
Takahisa Nakanishi ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cytomegalovirus Infection ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Hemorrhagic Colitis ◽  
Molecular Response ◽  
Pathological Findings ◽  
Major Molecular Response ◽  
Kinase Inhibitory Activity

A 69-year-old man with chronic-phase chronic myeloid leukemia was initially treated with 100 mg dasatinib once a day. Despite a major molecular response within 9 months, he developed hemorrhagic colitis 32 months after starting dasatinib. Colonoscopy identified multiple hemorrhagic ulcers in the transverse colon. The pathological findings indicated cytomegalovirus infection. Dasatinib was stopped and he was started on ganciclovir. Three months later, colonoscopy confirmed the disappearance of the hemorrhagic ulcers. Dasatinib is a second-generation tyrosine kinase inhibitor used to treat chronic myeloid leukemia. As a multi-kinase inhibitor that acts on SRC-family kinases, its broader off-target kinase-inhibitory activity may account for the adverse events of dasatinib. Although gastrointestinal bleeding is common in patients taking dasatinib, the combination of cytomegalovirus infection and hemorrhagic colitis in the absence of systemic immunodeficiency is rare. Based on this case of dasatinibinduced hemorrhagic colitis with cytomegalovirus infection, we describe a possible mechanism and effective treatment.

scholarly journals Priapism as the initial manifestation of chronic myeloid leukemia, a rare presentation

2021 ◽  
Vol 9 (7) ◽  
pp. 2102
Author(s):  
Regina De Miguel-Ibañez ◽  
Marcos Daniel Sanchez-Gonzalez ◽  
Diana Arlett Herrera-Madrid
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Myeloproliferative Neoplasm ◽  
Rare Presentation ◽  
Initial Manifestation ◽  
Ischemic Priapism ◽  
Age Of Diagnosis ◽  
Urological Emergency ◽  
Adequate Management

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with a median age of diagnosis in Mexico of 40 years. The initial manifestations are varied; however, priapism is a very rare entity associated to CML. We report the case of an 18-year-old male with an 8-hour episode of ischemic priapism managed with cavernous lavage, achieving complete flaccidity of the penis. The patient was diagnosed with CML, initiating cytoreduction with hydroxycarbamide and after having molecular confirmation, we started treatment with a tyrosine kinase inhibitor. The patient was discharged in excellent conditions, without sequelae of erectile dysfunction, all this attributed to the time of evolution, the adequate management of the urological emergency and the prompt identification and treatment of the precipitating condition.

scholarly journals A Case of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia, Chronic Phase with ASXL1 Mutation

2020 ◽  
Vol 13 (1) ◽  
pp. 449-455
Author(s):  
Osamu Imataki ◽  
Tomoya Ishida ◽  
Hiroyuki Kubo ◽  
Makiko Uemura ◽  
Yasuhito Nanya ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Disease Progression ◽  
Molecular Mechanism ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Graft Versus Host

Hematological malignancies, including chronic myeloid leukemia (CML), exhibit ASXL1 mutations; however, the function and molecular mechanism of these mutations remain unclear. ASXL1 was originally identified as tumor suppressor gene, in which loss of function causes myelodysplastic syndrome (MDS). ASXL1 mutations are common and associated with disease progression in myeloid malignancies including MDS, acute myeloid leukemia, and similarly in CML. In MDS, ASXL1 mutations have been associated with poor prognosis; however, the impact of ASXL1 mutations in CML has not been well described. A 31-year-old male was diagnosed as CML-chronic phase (CP). Laboratory findings showed a white blood cell count of 187,200/µL, with asymptomatic splenomegaly. Blast count was 5.0% in peripheral blood and 7.3% in bone marrow. There was no additional chromosomal abnormality except for t(9;22)(q34;q11.2) by chromosomal analysis. At onset, the Sokal score was 1.4, indicating high risk. The patient received tyrosine kinase inhibitor (TKI) therapy, comprising nilotinib ∼600 mg/day, bosutinib ∼600 mg/day, ponatinib ∼45 mg/day, and dasatinib ∼100 mg/day. Nevertheless, after 1.5 years of continuous TKI therapy, the best outcome was a hematological response. Although additional chromosomal aberrations and ABL1 kinase mutations were analyzed repeatedly before and during TKI therapy, known genetic abnormalities were not detected. Thereafter, the patient underwent bone marrow transplantation from an HLA 7/8 matched unrelated donor (HLA-Cw 1 locus mismatch, graft-versus-host direction). The patient achieved neutrophil engraftment, 18 days after transplantation, leading to complete remission with an undetectable level of BCR-ABL1 mRNA. The patient, however, died from graft-versus-host disease and thrombotic microangiopathy after 121 days. Gene sequence analysis of his CML cell before stem cell transplantation revealed ASXL1 mutations. Physiologically, ASXL1 contributes to epigenetic regulation. In the CML-CP patient in this case report, ASXL1 mutation conferred resistance to TKI through obscure resistance mechanisms. Even though a molecular mechanism for TKI resistance in ASXL1 mutation in CML has remained obscure, epigenetic modulation is a plausible mode of CML disease progression. The clinical impact including prognosis of ASXL1 for CML is underscored. And the treatment strategy of CML with ASXL1 mutation has not been established. A discussion of this case was expected to facilitate treatment options.

scholarly journals Chidamide Combined with Decitabine Synergistically Induce Apoptosis of Acute Myeloid Leukemia By up-Regulating Perp gene In Vivo and in Vitro

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 536-536
Author(s):  
Qing Li ◽  
Yunfan Yang ◽  
Yu Wu
Keyword(s):  
Cell Lines ◽  
Drug Combination ◽  
Transcriptome Sequencing ◽  
Myeloid Leukemia ◽  
Protein Levels ◽  
Apoptotic Protein ◽  
Induced Apoptosis ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) is a malignant clonal disease of hematopoietic stem cells. The long term survival of AML is not satisfactory, so new treatment should be explored. Here, we show that chidamide(CH), a histone deacetylase inhibitor, combined with decitabine(DE) induces apoptosis of AML cell lines and primary refractory/relapsed AML cells by up-regulating PERP. This may provide a new option for AML treatment. Methods and results: We first examined the half-inhibitory concentrations (IC50) of chidamide and decitabine against THP-1, MV4-11, HL60 and Kasumi-1 cell lines using MTT (Fig1 A-D). And the drug combination is performed according to the IC50. In the double-drug combination experiment, we used MTT to detect the effect of drugs on the proliferation of the four cell lines (Fig1 E-H), used calcusyn 2.0 software to calculate the synergistic effect (Fig2), flow cytometry to detect apoptosis (Fig3 A-D), and western blot to detect the pro-apoptotic protein (C-CASPASE 3 and C-CASPASE 9) and anti-apoptotic proteins (CASPASE 8, BCL-2 and BCL-XL) (Fig3 E-H). We found that chidamide combined with decitabine synergistically inhibited proliferation of AML cell lines, induced apoptosis, up-regulated pro-apoptotic protein levels and down-regulated anti-apoptotic protein levels. To investigate this combination therapeutic effect in vivo, we selected 5 refractory/relapsed AML patients, extracted primary AML cells, and used ATP chemiluminescence kit for drug sensitivity test. The results confirmed that four of the five patients with AML showed sensitivity to combinations (Fig4). To further explore the mechanism of action of CH combination with DE, we performed transcriptome sequencing (Fig5). Analysis of the sequencing results, the gene PERP, which shows the significant difference in the apoptotic pathway, was further examined. The PERP is a new member of the PMP-22/GAS3 family as an apoptosis-associated target of TP53. RT-QPCR and WB verified the role of PERP in apoptosis in DE and CH combination (Fig6). The results showed that the combination could up-regulate the PERP gene than the single drug. When we explored the role of the PERP gene in AML cell lines, we knocked down the PERP gene by lentivirus and detected cell proliferation after infection. Pretreated AML cell lines by lentivirus-infection (Fig7A-F), then we tested for proliferation (Fig7G-I) (Fig8A-C), apoptosis (Fig8D-E), and pro-apoptotic protein expression (Fig8G-I). The results showed that knocking down the PERP gene promoted the proliferation of AML cell lines and attenuated the sensitivity of AML cell lines to chemotherapeutic drugs. We also compare the mRNA level of PERP between 35 AML patients and 20 normal and found that the PERP mRNA of AML patients was significantly lower than the normal (Fig9). MV4-11 cells were exposed to CH and DE alone or in combination, and proteomic sequencing was performed to examine the effect of the drug on cellular protein. The result indicates to some extent that CH contributes more to the combined effect. And the drug causes changes in multiple pathways in the cell (Fig10). Conclusion: Our experiments revealed that CH combined with DE may have therapeutic effects on AML and, to some extent, reveal the mechanism of dual drug combination. Legends to figures Fig1. 50% inhibitory concentration (IC50) values of chidamide and decitabine alone treated AML cell lines. Fig2. Chidamide acts synergistically in AML with DE. Fig3. Chidamide in combination with decitabine significantly induced apoptosis in AML cell lines. Fig4. The sensitivity of relapsed or refractory AML primary cells to chidamide and decitabine alone or in combination. Fig5. Gene expression analysis showed an obvious difference based on treatment. Fig6. Verify transcriptome sequencing results by real-time QPCR and by western blotting with or without drug treatment. Fig7. The effect of down-regulation of PERP by Lentivirus-mediated RNAi on AML cells proliferation. Fig8. PERP knockdown causes AML cells to develop resistance to combination drugs. Fig9.The level of PERP mRNA in peripheral blood mononuclear cells of AML and normal humans. Fig10. Proteomics sequencing results show the differentially expressed protein and a cluster analysis of the functions or pathways enriched by differentially expressed proteins in GO and KEGG pathways compared to single agents. Disclosures No relevant conflicts of interest to declare.

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.

scholarly journals PD166326, a novel tyrosine kinase inhibitor, has greater antileukemic activity than imatinib mesylate in a murine model of chronic myeloid leukemia

Blood ◽  
2005 ◽  
Vol 105 (10) ◽  
pp. 3995-4003 ◽  
Author(s):  
Nicholas C. Wolff ◽  
Darren R. Veach ◽  
William P. Tong ◽  
William G. Bornmann ◽  
Bayard Clarkson ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Leukemia Cell ◽  
Antileukemic Activity

AbstractImatinib mesylate is highly effective in newly diagnosed chronic myeloid leukemia (CML), but BCR/ABL (breakpoint cluster region/abelson murine leukemia)–positive progenitors persist in most patients with CML treated with imatinib mesylate, indicating the need for novel therapeutic approaches. In this study, we have used the murine CML-like myeloproliferative disorder as a platform to characterize the pharmacokinetic, signal transduction, and antileukemic properties of PD166326, one of the most potent members of the pyridopyrimidine class of protein tyrosine kinase inhibitors. In mice with the CML-like disease, PD166326 rapidly inhibited Bcr/Abl kinase activity after a single oral dose and demonstrated marked antileukemic activity in vivo. Seventy percent of PD166326-treated mice achieved a white blood cell (WBC) count less than 20.0 × 109/L (20 000/μL) at necropsy, compared with only 8% of imatinib mesylate–treated animals. Further, two thirds of PD166326-treated animals had complete resolution of splenomegaly, compared with none of the imatinib mesylate–treated animals. Consistent with its more potent antileukemic effect in vivo, PD166326 was also superior to imatinib mesylate in inhibiting the constitutive tyrosine phosphorylation of numerous leukemia-cell proteins, including the src family member Lyn. PD166326 also prolonged the survival of mice with imatinib mesylate–resistant CML induced by the Bcr/Abl mutants P210/H396P and P210/M351T. Altogether, these findings demonstrate the potential of more potent Bcr/Abl inhibitors to provide more effective antileukemic activity. Clinical development of PD166326 or a related analog may lead to more effective drugs for the treatment of de novo and imatinib mesylate–resistant CML.

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