Targeting Mcl-1 and Other Bcl-2 Family Member Proteins in Cancer Therapy

Publication date: Available online 19 October 2018Source: Pharmacology &TherapeuticsAuthor(s): Ryuji Yamaguchi, Lydia Lartigue, Guy PerkinsAbstractRegulation of both the extrinsic and the mitochondria-dependent intrinsic apoptotic pathways plays a key role in the development of the hematopoietic system, for sustaining cell survival during generation of various cell types, in eliminating cells with dual identities such as CD4/CD8 double-positive cells1,2, for sustaining cells during the rapid clonal expansion phase3, as well as eliminating cells during the contraction phase4. The anti-apoptotic protein Mcl-1 is necessary for sustaining hematopoietic stem cells (HPS)5,6. The anti-apoptotic factors Mcl-1, Bcl-2, and Bcl-xL were also found to be over-expressed in acute myeloid leukemia (AML)7 and acute lymphocytic leukemia (ALL)8, suggesting that dis-regulated apoptotic processes could be a factor in the instigation of leukemia and/or its relapse. Molecules targeting these proteins were used as single agents to treat leukemia. However, by using a set of recently developed specific molecule inhibitors targeting anti-apoptotic proteins, distinct roles are being discovered for these anti-apoptotic proteins during hematopoietic and tumor development. Furthermore, using these inhibitors in proper combinations can effectively induce apoptosis in various solid tumors, even though each agent on its own cannot induce apoptosis in them. These new findings suggest that inhibiting anti-a...
Source: Pharmacology and Therapeutics - Category: Drugs & Pharmacology Source Type: research

Related Links:

Inversion or translocation of chromosome 3, specifically inv(3)(q21q26.2/t(3;3)(q21;q26.2), is a recurrent finding in myeloid malignancies. These rearrangements usually result in elevated expression of the proto-oncogene MECOM (EVI1) at 3q26.2, through juxtaposition with a distal GATA2 enhancer. [1,2] Acute myeloid leukemia (AML) with inv(3)/t(3;3) is classified by the WHO as a distinct entity which can present de novo or arise from prior myelodysplastic syndrome (MDS) and is associated with aggressive disease, minimal or no response to chemotherapy, and short survival [3,4].
Source: Cancer Genetics and Cytogenetics - Category: Genetics & Stem Cells Authors: Source Type: research
In this study, genetic mouse models and patient-derived xenografts demonstrated that JARID2 acts as a tumor suppressor in chronic myeloid disorders. Genetic deletion of Jarid2 either reduced overall survival of animals with MPNs or drove transformation to sAML, depending on the timing and context of co-operating mutations. Mechanistically, JARID2 recruits PRC2 to epigenetically repress self-renewal pathways in hematopoietic progenitor cells. These studies establish JARID2 as a bona fide hematopoietic tumor suppressor and highlight potential therapeutic targets.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research
In this study we interrogated the metabolome of human acute myeloid leukemia (AML) stem cells to elucidate properties relevant to therapeutic intervention. We demonstrate that amino acid uptake, steady-state levels, and catabolism are all elevated in the leukemia stem cell (LSC) population. Furthermore, LSCs isolated from de novo AML patients are uniquely reliant on amino acid metabolism for oxidative phosphorylation and survival. Pharmacological inhibition of amino acid metabolism reduces oxidative phosphorylation and induces cell death. In contrast, LSCs obtained from relapsed AML patients are not reliant on amino acid m...
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research
A total of 227 FLT3 ‐ITD sequences were analyzed from 227 Chinese adult de novo acute myeloid leukemia (AML) patients. ITD could be classified into 3 types based on molecular profiles. ITD integration sites in the hinge region or beta1‐sheet region are an unfavorable prognostic factor in adult AML patients with FLT 3‐ITD mutations. FMS ‐like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in hematological malignancies.FLT3 internal tandem duplication (FLT3‐ITD) mutations located in juxtamembrane domain (JMD) and tyrosine kinase domain 1 (TKD1) regions account for two‐thirds of allFLT3 mutat...
Source: Cancer Science - Category: Cancer & Oncology Authors: Tags: ORIGINAL ARTICLE Source Type: research
(Baylor College of Medicine) Acute myeloid leukemia (AML) cells expressing the NPM1 mutant gene are highly dependent on continued export of protein NPM1c to proliferate. This finding provides a rationale for testing nuclear export inhibitor therapeutics in NPM1-mutated AML.
Source: EurekAlert! - Cancer - Category: Cancer & Oncology Source Type: news
(University of Texas M. D. Anderson Cancer Center) A triple therapy combining two immune checkpoint inhibitors (ICPIs) with the standard-of-care chemotherapy, a hypomethylating agent called azacitidine, has shown promising results for treatment of relapsed or refractory acute myeloid leukemia (AML), according to findings from a Phase II study at The University of Texas MD Anderson Cancer Center.
Source: EurekAlert! - Cancer - Category: Cancer & Oncology Source Type: news
ConclusionsAmong patients withIDH1/2‐mutated AML, 2HG levels are highly specific for the mutational status at diagnosis, and they have prognostic relevance in patients receiving standard chemotherapy.
Source: Cancer - Category: Cancer & Oncology Authors: Tags: Original Article Source Type: research
l Ángel Sanz Marcos González-Díaz Jorge Sierra Ramon Mangues Isolda Casanova In recent years, several attempts have been made to identify novel prognostic markers in patients with intermediate-risk acute myeloid leukemia (IR-AML), to implement risk-adapted strategies. The non-receptor tyrosine kinases are proteins involved in regulation of cell growth, adhesion, migration and apoptosis. They associate with metastatic dissemination in solid tumors and poor prognosis. However, their role in haematological malignancies has been scarcely studied. We hypothesized that PTK2/FAK, PTK2B/PYK2, LYN o...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
(University of Colorado Anschutz Medical Campus) CU Cancer Center study shows that cancer stem cells switch from metabolizing sugar to metabolizing protein. Clinical trial based on this observation may revolutionize care for older adults with acute myeloid leukemia.
Source: EurekAlert! - Medicine and Health - Category: International Medicine & Public Health Source Type: news
AbstractAcute myeloid leukemia (AML) is the most common type of leukemia in adults. AML cells secrete angiogenic factors to remodel vasculature and acquire chemoresistance; however, antiangiogenic drugs are often ineffective in AML treatment. Cancer cell ‐derived exosomes can induce angiogenesis, but their role in vascular remodeling during AML is unclear. Here, we found that exosomes secreted by AML cells promoted proliferation and migration and tube‐forming activity of human umbilical vein endothelial cells (HUVECs), whereas HUVECs conferred c hemoresistance to AML cells. AML cell‐derived exosomes contained vascula...
Source: Journal of Cellular Physiology - Category: Cytology Authors: Tags: ORIGINAL RESEARCH ARTICLE Source Type: research
More News: Acute Leukemia | Acute Myeloid Leukemia | Cancer | Cancer & Oncology | Cancer Therapy | Drugs & Pharmacology | Leukemia | Mitochondria | Stem Cell Therapy | Stem Cells