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2.
Leukemia ; 33(1): 37-51, 2019 01.
Article in English | MEDLINE | ID: mdl-29884901

ABSTRACT

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy for which new therapeutic approaches are required. One such potential therapeutic strategy is to target the ubiquitin-like modifier-activating enzyme 1 (UBA1), the initiating enzyme in the ubiquitylation cascade in which proteins are tagged with ubiquitin moieties to regulate their degradation or function. Here, we evaluated TAK-243, a first-in-class UBA1 inhibitor, in preclinical models of AML. In AML cell lines and primary AML samples, TAK-243 induced cell death and inhibited clonogenic growth. In contrast, normal hematopoietic progenitor cells were more resistant. TAK-243 preferentially bound to UBA1 over the related E1 enzymes UBA2, UBA3, and UBA6 in intact AML cells. Inhibition of UBA1 with TAK-243 decreased levels of ubiquitylated proteins, increased markers of proteotoxic stress and DNA damage stress. In vivo, TAK-243 reduced leukemic burden and targeted leukemic stem cells without evidence of toxicity. Finally, we selected populations of AML cells resistant to TAK-243 and identified missense mutations in the adenylation domain of UBA1. Thus, our data demonstrate that TAK-243 targets AML cells and stem cells and support a clinical trial of TAK-243 in this patient population. Moreover, we provide insight into potential mechanisms of acquired resistance to UBA1 inhibitors.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Leukemia, Myeloid, Acute/drug therapy , Nucleosides/pharmacology , Sulfonamides/pharmacology , Ubiquitin-Activating Enzymes/antagonists & inhibitors , Xenograft Model Antitumor Assays , Animals , Cell Proliferation/drug effects , Endoplasmic Reticulum Stress/drug effects , Humans , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/pathology , Mice , Mice, SCID , Pyrazoles , Pyrimidines , Sulfides , Tumor Cells, Cultured
4.
Leuk Res ; 68: 22-28, 2018 05.
Article in English | MEDLINE | ID: mdl-29518628

ABSTRACT

We evaluated outcomes of 100 patients with high risk AML treated with Ida-FLAG induction as first-line therapy. 72 achieved remission with one cycle; 19 did not. High risk cytogenetics and TP53 mutations were associated with failure to achieve remission. In those reaching remission, allogeneic bone marrow transplantation was associated with better relapse-free and overall survival. Those not achieving remission with induction therapy were extremely unlikely to reach remission with further therapy and had a dismal prognosis. Exploratory molecular analysis confirmed persistence of the dominant genetic mutations identified at diagnosis. Ex vivo chemosensitivity did not demonstrate significant differences between responders and non-responders. Thus, Ida-FLAG induction has a high chance of inducing remission in patients with high risk AML. Those achieving remission require allogeneic transplantation to achieve cure; those not achieving remission rarely respond to salvage chemotherapy and have a dismal outcome. Alternatives to conventional chemotherapy must be considered in this group.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Induction Chemotherapy , Leukemia, Myeloid, Acute/drug therapy , Vidarabine/analogs & derivatives , Adolescent , Adult , Aged , Cytarabine/therapeutic use , Female , Genes, p53 , Granulocyte Colony-Stimulating Factor/therapeutic use , Humans , Idarubicin/therapeutic use , Leukemia, Myeloid, Acute/genetics , Male , Middle Aged , Mutation , Prognosis , Remission Induction , Retrospective Studies , Treatment Outcome , Vidarabine/therapeutic use , Young Adult
5.
Expert Opin Emerg Drugs ; 23(1): 51-62, 2018 03.
Article in English | MEDLINE | ID: mdl-29480034

ABSTRACT

INTRODUCTION: BCR-ABL-directed tyrosine kinase inhibitors (TKIs) have revolutionised therapy for chronic myeloid leukemia. However, despite the availability and efficacy of this class of agents, lifelong treatment is still required in a significant proportion of patients Areas covered: We give an overview of the currently available BCR-ABL-directed TKIs and other conventional therapies for CML. We proceed to review the current market and some of the scientific rationale for new drug development before outlining a number of novel therapies, considered broadly as immunotherapies and targeted agents. Published English-language literature was reviewed regarding currently available TKIs; clinical trials repositories were reviewed to identify novel agents recently investigated or under active study. Expert opinion: We recommend discussion with patients and enrolment on an appropriate clinical trial where feasible. In situations where no trials are available, or if patients decline enrolment, we recommend use of an appropriate BCR-ABL directed TKI, selected on the basis of an evaluation of patient risk factors and side effect profile. Allogeneic stem cell transplant continues to have a role though this is generally limited to cases with advanced phases of disease or in cases with resistance-conferring mutations.


Subject(s)
Antineoplastic Agents/therapeutic use , Drug Design , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Hematopoietic Stem Cell Transplantation/methods , Humans , Immunotherapy/methods , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Molecular Targeted Therapy , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use
6.
JCI Insight ; 2(18)2017 09 21.
Article in English | MEDLINE | ID: mdl-28931762

ABSTRACT

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a poor outcome; overall survival is approximately 35% at two years and some subgroups have a less than 5% two-year survival. Recently, significant improvements have been made in our understanding of AML biology and genetics. These fundamental discoveries are now being translated into new therapies for this disease. This review will discuss recent advances in AML biology and the emerging treatments that are arising from biological studies. Specifically, we will consider new therapies that target molecular mutations in AML and dysregulated pathways such as apoptosis and mitochondrial metabolism. We will also discuss recent advances in immune and cellular therapy for AML.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Translational Research, Biomedical , Epigenesis, Genetic , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Molecular Targeted Therapy , Mutation
7.
Am J Pathol ; 187(7): 1512-1522, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28502479

ABSTRACT

Myeloproliferative neoplasms (MPNs) are a group of related clonal hemopoietic stem cell disorders associated with hyperproliferation of myeloid cells. They are driven by mutations in the hemopoietic stem cell, most notably JAK2V617F, CALR, and MPL. Clinically, they have the propensity to progress to myelofibrosis and transform to acute myeloid leukemia. Megakaryocytic hyperplasia with abnormal features are characteristic, and it is thought that these cells stimulate and drive fibrotic progression. The biological defects underpinning this remain to be explained. In this study we examined the megakaryocyte genome in 12 patients with MPNs to determine whether there are somatic variants and whether there is any association with marrow fibrosis. We performed targeted next-generation sequencing for 120 genes associated with myeloid neoplasms on megakaryocytes isolated from aspirated bone marrow. Ten of the 12 patients had genomic defects in megakaryocytes that were not present in nonmegakaryocytic hemopoietic marrow cells from the same patient. The greatest allelic burden was in patients with increased reticulin deposition. The megakaryocyte-unique mutations were predominantly in genes that regulate chromatin remodeling, chromosome alignment, and stability. These findings show that genomic abnormalities are present in megakaryocytes in MPNs and that these appear to be associated with progression to bone marrow fibrosis.


Subject(s)
Bone Marrow Neoplasms/genetics , Leukemia, Myeloid, Acute/genetics , Myeloproliferative Disorders/genetics , Primary Myelofibrosis/genetics , Alleles , Bone Marrow/pathology , Bone Marrow Neoplasms/pathology , Gene Frequency , Genomics , High-Throughput Nucleotide Sequencing , Humans , Janus Kinase 2/genetics , Leukemia, Myeloid, Acute/pathology , Megakaryocytes/pathology , Mutation , Myeloid Cells/pathology , Myeloproliferative Disorders/pathology , Primary Myelofibrosis/pathology , Receptors, Thrombopoietin/genetics , Sequence Analysis, DNA
8.
J Clin Pathol ; 2016 Apr 08.
Article in English | MEDLINE | ID: mdl-27060176

ABSTRACT

AIMS: Megakaryocyte expansion in myeloproliferative neoplasms (MPNs) is due to uncontrolled proliferation accompanied by dysregulation of proapoptotic and antiapoptotic mechanisms. Here we have investigated the intrinsic and extrinsic apoptotic pathways of megakaryocytes in human MPNs to further define the mechanisms involved. METHODS: The megakaryocytic expression of proapoptotic caspase-8, caspase-9, Diablo, p53 and antiapoptotic survivin proteins was investigated in bone marrow specimens of the MPNs (n=145) and controls (n=15) using immunohistochemistry. The megakaryocyte percentage positivity was assessed by light microscopy and correlated with the MPN entity, JAK2V617F/CALR mutation status and platelet count. RESULTS: The proportion of megakaryocytes in the MPNs expressing caspase-8, caspase-9, Diablo, survivin and p53 was significantly greater than controls. A greater proportion of myeloproliferative megakaryocytes expressed survivin relative to its reciprocal inhibitor, Diablo. Differences were seen between myelofibrosis, polycythaemia vera and essential thrombocythaemia for caspase-9 and p53. CALR-mutated cases had greater megakaryocyte p53 positivity compared to those with the JAK2V617F mutation. Proapoptotic caspase-9 expression showed a positive correlation with platelet count, which was most marked in myelofibrosis and CALR-mutated cases. CONCLUSIONS: Disruptions targeting the intrinsic apoptotic cascade promote megakaryocyte hyperplasia and thrombocytosis in the MPNs. There is progressive dysfunction of apoptosis as evidenced by the marked reduction in proapoptotic caspase-9 and accumulation of p53 in myelofibrosis. The dysfunction of caspase-9, which is necessary for proplatelet formation, may be the mechanism for the excess thrombocytosis associated with CALR mutations. Survivin seems to be the key protein mediating the megakaryocyte survival signature in the MPNs and is a potential therapeutic target.

9.
J Clin Pathol ; 69(6): 543-6, 2016 Jun.
Article in English | MEDLINE | ID: mdl-26984929

ABSTRACT

BACKGROUND: Transforming growth factor α (TGFα) is a peptide growth factor known to be expressed in normal haemopoiesis. It is also expressed in a range of epithelial neoplasms but has not been assessed in haemopoietic malignancies. We have performed an immunohistochemical evaluation of TGFα in acute and chronic myeloid malignancies. METHODS: TGFα expression was semiquantitatively assessed in 69 normal bone marrow trephines and 157 cases of myeloid malignancy using an immunohistochemical approach. RESULTS: Blast cells of myeloid origin in acute myeloid leukaemia (AML), myelodysplasia and accelerated and blast phases of chronic myeloid leukaemia (CML) were TGFα positive. In acute promyelocytic leukaemia the neoplastic cells had significantly weaker TGFα expression than seen in other forms of AML. The blast cells in CML-accelerated and blast phases were positive with similar expression to AML. CONCLUSIONS: TGFα is expressed in neoplastic myeloblasts and could, therefore, be used as blast cell biomarker in diagnostic haematopathology. In addition, TGFα immunohistochemistry may be of use in identifying a therapeutic target.


Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Leukemia, Myeloid, Acute/metabolism , Myelodysplastic Syndromes/metabolism , Myeloproliferative Disorders/metabolism , Transforming Growth Factor alpha/metabolism , Biomarkers/metabolism , Bone Marrow/pathology , Hematopoiesis , Humans , Immunohistochemistry , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Promyelocytic, Acute/diagnosis , Leukemia, Promyelocytic, Acute/metabolism , Leukocytes/pathology , Myelodysplastic Syndromes/diagnosis , Myeloproliferative Disorders/diagnosis
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