Similar Datasets
Project description:Following nearly five decades with few approved therapies for acute myeloid leukemia (AML), the last three years have brought stellar progress with the U.S. Food and Drug Administration approving a number of new therapies for AML patients. Despite these advances, there are several high-risk patient AML populations with dismal survival on the order of months including those with primary refractory disease, those whose AML developed from an antecedent hematologic disorder, and those with high risk cytogenetic or mutational profiles (such as TP53 mutations or a complex karyotype). Furthermore, therapeutic options are limited for those unfit to receive cytotoxic chemotherapy due to age or co-morbidities. These treatment challenges clearly illustrate the need for improved therapeutic approaches in AML. Here we identify that antibody therapies for AML can be enhanced via optimization of (1) Fab target selection, and (2) engineering the Fc portion of the antibody to maximally engage receptors on immune effector cells. We demonstrate that antibodies targeting a novel AML-specific cell surface marker known as U5 snRNP200 have therapeutic efficacy in AML. Finally, we performed a whole-genome CRISPR screen to identify mechanisms by which U5 snRNP200 traffic to the cell surface. This revealed a requirement for cell-surface CD32a to enable U5 snRNP200 cell membrane localization.
2022-12-02 | GSE205028 | GEO
Project description:Following nearly five decades with few approved therapies for acute myeloid leukemia (AML), the last three years have brought stellar progress with the U.S. Food and Drug Administration approving a number of new therapies for AML patients. Despite these advances, there are several high-risk patient AML populations with dismal survival on the order of months including those with primary refractory disease, those whose AML developed from an antecedent hematologic disorder, and those with high risk cytogenetic or mutational profiles (such as TP53 mutations or a complex karyotype). Furthermore, therapeutic options are limited for those unfit to receive cytotoxic chemotherapy due to age or co-morbidities. These treatment challenges clearly illustrate the need for improved therapeutic approaches in AML. Here we identify that antibody therapies for AML can be enhanced via optimization of (1) Fab target selection, and (2) engineering the Fc portion of the antibody to maximally engage receptors on immune effector cells. We demonstrate that antibodies targeting a novel AML-specific cell surface marker known as U5 snRNP200 have therapeutic efficacy in AML. Finally, we performed a whole-genome CRISPR screen to identify mechanisms by which U5 snRNP200 traffic to the cell surface. This revealed a requirement for cell-surface CD32a to enable U5 snRNP200 cell membrane localization.
2022-12-08 | GSE220473 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-03-16 | GSE222169 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-09-20 | GSE108316 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-03-10 | GSE168463 | GEO
Project description:Acute myeloid leukemia (AML) is associated with a poor survival rate, and there is an urgent need for novel and more efficient therapies, ideally targeting AML stem cells that are essential for maintaining the disease. The interleukin 1 receptor accessory protein (IL1RAP; IL1R3) is expressed on candidate leukemic stem cells in the majority of AML patients, but not on normal hematopoietic stem cells. We show here that monoclonal antibodies targeting IL1RAP have strong antileukemic effects in xenograft models of human AML. We demonstrate that effector-cell-mediated killing is essential for the observed therapeutic effects and that natural killer cells constitute a critical human effector cell type. Because IL-1 signaling is important for the growth of AML cells, we generated an IL1RAP-targeting antibody capable of blocking IL-1 signaling and show that this antibody suppresses the proliferation of primary human AML cells. Hence, IL1RAP can be efficiently targeted with an anti-IL1RAP antibody capable of both achieving antibody-dependent cellular cytotoxicity and blocking of IL-1 signaling as modes of action. Collectively, these results provide important evidence in support of IL1RAP as a target for antibody-based treatment of AML.
| S-EPMC4553807 | biostudies-other
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-03-01 | E-GEOD-74651 | biostudies-arrayexpress
Project description:Acute Myeloid Leukemia (AML) is an extremely heterogeneous group of hematological neoplasms, for which allogeneic stem cell transplantation (HSCT) still represents the only potentially curative option in the majority of cases. However, elderly age and clinically severe comorbidities may often exclude a wide amount of patients from this therapeutic approach, underlying the urgent need for alternative strategies. Thanks to the introduction of advanced high-throughput techniques, light is being shed on the pathogenesis of AML, identifying molecular recurrent mutations as responsible for the onset, as well as progression, of disease. As a consequence, and in parallel, many new compounds, including targeted therapies (FMS-like tyrosine kinase 3 (FLT3) and Isocitrate dehydrogenase 1-2 (IDH1-2) inhibitors), have found a wide room of application in this setting, and are now available in daily practice, or in late phases of clinical development. Moreover, several further innovative molecules are currently under investigation, and promising results for many of them have already been reported. In this review, we will present an update on the most relevant molecular alterations of AML, focusing on the most frequent genomic mutations of the disease, for which compounds have been approved or are still currently under investigation.
| S-EPMC6600275 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-11-01 | GSE129863 | GEO
Project description:Despite substantial gains in our understanding of the genomics of acute myelogenous leukemia (AML), patient survival remains unsatisfactory especially among the older age group. T cell-based therapy of lymphoblastic leukemia is rapidly advancing; however, its application in AML is still lagging behind. Bispecific antibodies can redirect polyclonal effector cells to engage chosen targets on leukemia blasts. When the effector cells are natural-killer cells, both antibody-dependent and antibody-independent mechanisms could be exploited. When the effectors are T cells, direct tumor cytotoxicity can be engaged followed by a potential vaccination effect. In this review, we summarize the AML-associated tumor targets and the bispecific antibodies that have been studied. The potentials and limitations of each of these systems will be discussed.
| S-EPMC5386336 | biostudies-literature