RESUMO
Although great advances have been made in understanding the pathobiology of mixed lineage leukemia-rearranged (MLL-r) leukemias, therapies for this leukemia have remained limited, and clinical outcomes remain bleak. In order to identify novel targets for immunotherapy treatments, we compiled a lineage-independent MLL-r leukemia gene signature using publicly available data sets. Data from large leukemia repositories were filtered through the in silico human surfaceome, providing a list of highly predicted cell surface proteins overexpressed in MLL-r leukemias. LAMP5, a lysosomal associated membrane protein, is expressed highly and specifically in MLL-r leukemia. We found that LAMP5 is a direct target of the oncogenic MLL-fusion protein. LAMP5 depletion significantly inhibited leukemia cell growth in vitro and in vivo. Functional studies showed that LAMP-5 is a novel modulator of innate-immune pathways in MLL-r leukemias. Downregulation of LAMP5 led to inhibition of NF-kB signaling and increased activation of type-1 interferon signaling downstream of Toll-like receptor/interleukin 1 receptor activation. These effects were attributable to the critical role of LAMP-5 in transferring the signal flux from interferon signaling endosomes to pro-inflammatory signaling endosomes. Depletion of IRF7 was able to partially rescue the cell growth inhibition upon LAMP5 downregulation. Lastly, LAMP-5 was readily detected on the surface of MLL-r leukemia cells. Targeting surface LAMP-5 using an antibody-drug conjugate leads to significant cell viability decrease specifically in MLL-r leukemias. Overall, based on the limited expression throughout human tissues, we postulate that LAMP-5 could potentially serve as an immunotherapeutic target with a wide therapeutic window to treat MLL-r leukemias.
Assuntos
Leucemia Aguda Bifenotípica , Leucemia , Histona-Lisina N-Metiltransferase/genética , Humanos , Imunoterapia , Leucemia/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismoRESUMO
Cardiotoxicity linked with hematopoietic stem cell transplantation (HSCT) is a well-described phenomenon associated with an increased mortality risk; however, the majority of cardiac events present over 100 days following transfusion and are often attributed to graft-versus-host disease or pre-treatment conditioning by chemotherapy with or without radiation therapy. Here, we present the case of a 60-year-old female with a medical history of chronic lymphocytic leukemia complicated by a myelodysplastic syndrome that progressed to acute myeloid leukemia who developed chest pain immediately following an allogeneic HSCT. Electrocardiogram showed dynamic ST-depressions in leads V3-5 without evidence of reciprocal changes. Transthoracic echocardiography revealed pericardial effusion without signs of tamponade. The patient was thought to have acute pericarditis and was subsequently treated with high-dose intravenous methylprednisolone with a taper for two weeks. Her symptoms promptly subsided, and the pericardial effusion resolved on repeat echocardiography, which confirmed the diagnosis. Acute pericarditis is a rarely described complication of HSCT that is fatal if left untreated and prompts urgent management. This atypical case of acute pericarditis in the early post-transplant phase highlights the importance of cardiac stratification in patients with active malignancy undergoing treatment. It would suggest a potential benefit in closely monitoring high-risk individuals who have a history of coronary artery disease, smoking, or pericarditis in the pre-engraftment phase of transplantation.
RESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Despite growing awareness of the biologic features underlying MLL-rearranged leukemia, targeted therapies for this leukemia have remained elusive and clinical outcomes remain dismal. MBNL1, a protein involved in alternative splicing, is consistently overexpressed in MLL-rearranged leukemias. We found that MBNL1 loss significantly impairs propagation of murine and human MLL-rearranged leukemia in vitro and in vivo. Through transcriptomic profiling of our experimental systems, we show that in leukemic cells, MBNL1 regulates alternative splicing (predominantly intron exclusion) of several genes including those essential for MLL-rearranged leukemogenesis, such as DOT1L and SETD1A. We finally show that selective leukemic cell death is achievable with a small molecule inhibitor of MBNL1. These findings provide the basis for a new therapeutic target in MLL-rearranged leukemia and act as further validation of a burgeoning paradigm in targeted therapy, namely the disruption of cancer-specific splicing programs through the targeting of selectively essential RNA binding proteins.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Leucemia/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Ligação a RNA/metabolismo , Processamento Alternativo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Transplante de Medula Óssea , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Conjuntos de Dados como Assunto , Técnicas de Silenciamento de Genes , Rearranjo Gênico , Histona-Lisina N-Metiltransferase/genética , Humanos , Íntrons/genética , Leucemia/tratamento farmacológico , Leucemia/patologia , Camundongos , Camundongos Knockout , Cultura Primária de Células , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/genética , RNA-Seq , Quimeras de Transplante , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Langerhans cell histiocytosis (LCH) is a rare hematologic neoplasm characterized by a clonal proliferation of Langerhans-like cells. Genomic profiling has identified recurrent somatic activating mutations in the mitogen-activated protein kinase pathway, which are targetable by small-molecule inhibitors. However, key questions such as the curative potential of targeted therapy and the cell of origin remain unanswered. In this study, we describe clinical outcomes of a series of pediatric patients with multisystem BRAF V600E-mutant LCH, as well as the results of accompanying murine xenograft experiments. Four infants with LCH (range, 7-11 months at diagnosis) and secondary hemophagocytic lymphohistiocytosis were referred to our institution and subsequently treated with the BRAF V600E-specific inhibitor dabrafenib. All patients achieved complete clinical responses by 8 weeks of therapy, with remissions lasting a median of 36 months (range, 27-42 months). One infant successfully discontinued therapy long-term upon achieving a molecular response by real-time quantitative polymerase chain reaction (RT-qPCR). We further characterized the disease-propagating cell population in a subset of these patients by transplanting whole bone marrow into immunodeficient mice. Xenografted animals exhibited decreased survival with hematologic abnormalities, splenomegaly, and histiocytic infiltrates in the bone marrow resembling human disease. This process could also be secondarily transplanted, resulting in a comparable disease latency with similar histologic findings. These data further support the presence of a disease-initiating cell in the bone marrow compartment. We demonstrate that despite aggressive disease behavior in a xenograft model, these patients can achieve sustained clinical remissions with targeted monotherapy, with a select subset achieving molecular responses by RT-qPCR.