BOK promotes erythropoiesis in a mouse model of myelodysplastic syndrome

AbstractMyelodysplastic syndromes are clonal hematopoietic stem cell disorders characterized by cytopenia and intramedullary apoptosis. BCL-2 Ovarian Killer (BOK) is a pro-apoptotic member of the BCL-2 family of proteins which, when stabilized from endoplasmic reticulum-associated degradation (ERAD), induces apoptosis in response to ER stress. Although ER stress appropriately activates the unfolded protein response (UPR) in BOK-disrupted cells, the downstream effector signaling that includes ATF4 is defective. We used Nup98-HoxD13 (NHD13) transgenic mice to evaluate the consequences of BOK loss on hematopoiesis and leukemogenesis. Acute myeloid leukemia developed in 36.7% of NHD13 mice with aBok gene knockout between the age of 8 and 13  months and presented a similar overall survival to the NHD13 mice. The loss of BOK exacerbated anemia in NHD13 mice, and NHD13/BOK-deficient mice exhibited significantly lower hemoglobin, lower mean cell hemoglobin concentration, and higher mean cell volume than NHD13 mice. Hematopoietic progenito r cell assays revealed a decreased amount of erythroid progenitor stem cells (BFU-E) in the bone marrow of NHD13-transgenic/BOK-deficient mice. RT-qPCR analysis demonstrated decreased mean value of ATF4 in the erythroid progenitors of NHD13 and NHD13/BOK-deficient mice. Our results suggest that in a ddition to induction of apoptosis in response to ER stress, BOK may regulate erythropoiesis when certain erythroid progenitors experience cell stre...
Source: Annals of Hematology - Category: Hematology Source Type: research

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Allogeneic HLA-matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) for adults with acquired severe aplastic anemia (SAA) is currently recommended after failure to respond to a course of immunosuppressive therapy (IST) 1,2. This guidance reflects the historical developments in HSCT and IST, and the improving outcomes of MUD HSCT over time. Although SAA patients are surviving long term after both HSCT and IST, the long-term complications of clonal transformation to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) and hemolytic PNH after IST in up to 15-26% of patients at 10 years are notable 3-7.
Source: Biology of Blood and Marrow Transplantation - Category: Hematology Authors: Source Type: research
Allogeneic HLA-matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) for adults with acquired severe aplastic anemia (SAA) is currently recommended after failure to respond to a course of immunosuppressive therapy (IST) [1,2]. This guidance reflects the historical developments in HSCT and IST, as well as the improving outcomes of MUD HSCT over time. Although patients with SAA are surviving long term after both HSCT and IST, the long-term complications of clonal transformation to myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) and hemolytic paroxysmal nocturnal hemoglobinuria (PNH)...
Source: Biology of Blood and Marrow Transplantation - Category: Hematology Authors: Source Type: research
In conclusion, we showed hypermethylation of CpGs as a novel mechanism of action for DNMTi agents and identified 638 hypermethylated molecular targets (CpGs) common to decitabine and azacytidine therapy. These novel results suggest that hypermethylation of CpGs should be considered when predicting the DNMTi responses and side effects in cancer patients. Introduction DNA methyltransferase inhibitors (DNMTi) are widely used as chemical tools for hypomethylating the genome, with an aim to understand the role of DNA methylation in multiple processes (e.g., X-chromosome inactivation and DNA imprinting) and as an anti-ca...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
In this study, we characterized MDS-associated SRSF2 mutants (P95H, P95L, and P95R). We found that those mutants and wild-type SRSF2 proteins showed nuclear localization in HeLa cells. In vitro splicing reaction also revealed that mutant proteins associated with both precursor and spliced mRNAs, suggesting that the mutants directly participate in splicing. We established the human myeloid leukemia K562 cell lines that stably expressed myc-tagged wild-type or mutant SRSF2 proteins, and then performed RNA-sequence to analyze the splicing pattern of each cell line. The results revealed that both wild-type and mutants affected...
Source: Frontiers in Genetics - Category: Genetics & Stem Cells Source Type: research
Myelodysplastic syndromes (MDS) are clonal diseases defined by clinical, morphologic, and genetic features often shared by related myeloid disorders. The diagnostic boundaries between these diseases can be arbitrary and not necessarily reflective of underlying disease biology or outcomes. In practice, measures that distinguish MDS from related disorders may be difficult to quantify and can vary as disease progression occurs. Patients may harbor findings that are not consistent with a single diagnostic category. Several overlap disorders have been formally described, such as the myelodysplastic/myeloproliferative neoplasms ...
Source: Blood - Category: Hematology Authors: Tags: Hematopoiesis and Stem Cells, Myeloid Neoplasia, Review Articles, Review Series, Clinical Trials and Observations Source Type: research
This study may open up new potential therapeutic avenues for the treatment of patients with chronic infection, inflammatory diseases, and cancer.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - Category: Hematology Authors: Tags: 506. Hematopoiesis and Stem Cells: Microenvironment, Cell Adhesion, and Stromal Stem Cells Source Type: research
Conclusions. ISV is widely used in hematological pts with IFI also in diseases other than acute myeloid leukemia and it is overall well tolerated. ORR to ISV is at least comparable with other antifungal agents. A rec/ref underlying hematological disease impacts both on OS and response to ISV, while having an IFI refractory to other antifungal agents including azoles does not seem to compromise the response to ISV, although this promising result should be confirmed in prospective studies and larger groups of patients.DisclosuresBusca: Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Sp...
Source: Blood - Category: Hematology Authors: Tags: 203. Lymphocytes, Lymphocyte Activation, and Immunodeficiency, including HIV and Other Infections: Poster III Source Type: research
ConclusionOur first-in-human clinical trial demonstrates promising efficacy of cCAR therapy in treating patients with relapsed/ refractory AML. cCAR is able to eradicate leukemia blasts and leukemia stem cells, exerting a profound tumor killing effect that is superior to single target CAR T cell therapies. cCAR is also shown to induce total myeloid ablation in bone marrow, suggesting that it may act as a safer alternative to avoid the severe toxicities caused by standard bone marrow ablation regimens without sacrificing the anti-tumor efficacy. This strategy will likely benefit patients who are unable to tolerate total bod...
Source: Blood - Category: Hematology Authors: Tags: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Immunotherapy Source Type: research
Background:The prognosis for acute myeloid leukemia (AML) patients age>60 years is poor. Rapid pre-treatment identification of molecular disease subsets may allow specific targeting with novel agents, presenting an opportunity to improve outcomes. The Leukemia and Lymphoma Society (LLS)-sponsored Beat AML master trial was initiated for previously untreated AML patients ≥60 years, with treatment assignment to a sub-study (S1, S2, etc.) based upon cytogenetics and dominant clone by next generation sequencing; patients with multiple mutations are assigned a sub-study according to variant allele frequency and a predeterm...
Source: Blood - Category: Hematology Authors: Tags: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster III Source Type: research
CONCLUSIONSOur data shows how incorporating the patient voice early on in PRO measurement selection and a conceptually-driven approach to the development of customized item sets can lead to more fit-for-purpose PRO measures to be used in the context of clinical trials of patients with cancer. Specifically, while the QLQ-C30 may be a satisfactory PRO instrument for use in people with hematological stem cell disorders, it can be made more targeted and disease-specific by carefully utilizing mixed methods and selecting supplemental items from the EORTC item library. This patient-reported online survey provides early evidence,...
Source: Blood - Category: Hematology Authors: Tags: 904. Outcomes Research-Malignant Conditions: Poster III Source Type: research
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