Assuntos
Antígeno B7-H1 , Amplificação de Genes/efeitos dos fármacos , Hidroxiureia/efeitos adversos , Janus Quinase 2 , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Segunda Neoplasia Primária , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Humanos , Hidroxiureia/administração & dosagem , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Leucemia Mieloide Aguda/induzido quimicamente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Masculino , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/metabolismoRESUMO
Aggressive myeloid leukemias such as blast crisis chronic myeloid leukemia and acute myeloid leukemia remain highly lethal. Here we report a genome-wide in vivo CRISPR screen to identify new dependencies in this disease. Among these, RNA-binding proteins (RBPs) in general, and the double-stranded RBP Staufen2 (Stau2) in particular, emerged as critical regulators of myeloid leukemia. In a newly developed knockout mouse, loss of Stau2 led to a profound decrease in leukemia growth and improved survival in mouse models of the disease. Further, Stau2 was required for growth of primary human blast crisis chronic myeloid leukemia and acute myeloid leukemia. Finally, integrated analysis of CRISPR, eCLIP and RNA-sequencing identified Stau2 as a regulator of chromatin-binding factors, driving global alterations in histone methylation. Collectively, these data show that in vivo CRISPR screening is an effective tool for defining new regulators of myeloid leukemia progression and identify the double-stranded RBP Stau2 as a critical dependency of myeloid malignancies.
Assuntos
Crise Blástica , Leucemia Mieloide Aguda , Proteínas do Tecido Nervoso , Proteínas de Ligação a RNA , Animais , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Genoma , Leucemia Mieloide Aguda/genética , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas de Ligação a RNA/genéticaRESUMO
CONTEXT.: Stand-alone clinical sites (eg, infusion centers) are becoming increasingly common. These sites require timely hematology analysis. Here we compare performance and costs of currently available analysis configurations with special focus on a proposed alternative using a minimal hematology analyzer plus a digital imaging device, allowing for remote oversight and interpretation. OBJECTIVES.: To determine whether low-volume laboratories might realize savings while gaining function by substituting commonly used configurations with a proposed alternative. DESIGN.: To evaluate the performance of the proposed alternative configuration, blood counts with automated differentials produced by a Sysmex XE5000 (complete blood count reference method) were compared with cell counts from the Sysmex pocH-100i, CellaVision DM96 preclassified differentials, and DM96 reclassified differentials (differential reference method) by using standard regression analyses, 95% CIs, and truth tables. Financial cost modeling used staffing practices, test volumes, and smear production rates observed at remote clinics performing on-site hematology analysis within the University of California at San Diego Health system. RESULTS.: Differential blood count parameters showed excellent correlation between the XE5000 and preclassification DM96 with R2 > 0.95. For blasts/abnormal cells, immature granulocytes, and nucleated red blood cells, the DM96 showed higher sensitivity and similar specificity to the XE5000. Cost modeling revealed that decreased personnel costs through remote monitoring of results facilitated by the DM96 would lead to lower operational costs relative to more conventional analysis configurations. CONCLUSIONS.: A digital imaging instrument with an inexpensive hematology analyzer provides similar information to a complex hematology analyzer and allows remote review of the blood smear findings by experts, leading to significant cost savings.
Assuntos
Processamento Eletrônico de Dados/instrumentação , Testes Hematológicos/instrumentação , Hematologia/instrumentação , Telemedicina/instrumentação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Contagem de Células Sanguíneas/instrumentação , Serviços de Laboratório Clínico , Feminino , Humanos , Laboratórios , Contagem de Leucócitos/instrumentação , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Adulto JovemRESUMO
BACKGROUND: To optimize precision of nucleated blood cell counting, the clinical laboratory scientist should post the automated differential rather than the manual differential if the former is within the 95% CI of the latter, as determined by the "Rumke statistic." The objective of this study was to determine the potential impact of real-time, computer-assisted use of Rumke statistics for more judicious use of the automated vs digitally imaged, manual differential. METHODS: Complete blood counts with automated differentials produced by a XE5000™ hematology analyzer (Sysmex) were compared with both the DM96 (CellaVision™ AB) preclassification differentials and the posted reclassified manual differentials, using the Rumke 95% CIs as calculated using the Clopper-Pearson method. RESULTS: A total of 44.7% of manual differentials had no statistical or clinical justification over the automated differential. In addition, 31.1% of manual differentials had statistical discrepancies between the instrument absolute neutrophil count (IANC) and manual absolute neutrophil count (ANC). Nineteen of these IANC/manual ANC discrepant samples had ANCs below 1500/µL, a decision level for cancer treatment. Holding the IANC when it is less than 2000/µL until after manual smear review would have prevented the posting of any IANC vs manual ANC discrepant results at the 1500/µL ANC decision threshold. CONCLUSIONS: A real-time operator alert concerning the statistical identity of imaging device differentials vs automated differentials could have reduced manual differentials by nearly 45%. Not posting unnecessary manual differentials for the cases with IANC/manual ANC discrepancies would have likely reduced clinical error/confusion.
Assuntos
Leucemia Linfocítica Granular Grande/etiologia , Mieloma Múltiplo/etiologia , Neoplasias Primárias Múltiplas/etiologia , Humanos , Leucemia Linfocítica Granular Grande/imunologia , Leucemia Linfocítica Granular Grande/metabolismo , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/metabolismo , Neoplasias Primárias Múltiplas/imunologia , Neoplasias Primárias Múltiplas/metabolismoRESUMO
Double minute chromosomes (DMs), although relatively frequently encountered in solid tumors, are rare in hematologic neoplasms such as acute myeloid leukemia (AML), and even rarer in lymphoid neoplasms. t(3;3)(q26.2;q21) is a very rare genetic alteration observed in myeloid neoplasm. Herein we report an interesting and unique case of concomitant C-MYC DMs and t(14;18)-containing large B-cell lymphoma, which was successfully treated with R-hyper-CVAD; unfortunately, the patient has developed a therapy-related AML (t-AML) 2 years since the start of his lymphoma treatment. His t-AML contains both t(3;3)(q26.2;q21) and monosomy 7, and the patient died of AML 10 months after the initial diagnosis of t-AML despite clinical remission. To the best of our knowledge, this is the first reported case of C-MYC DM-containing de novo large B-cell lymphoma, which was successfully treated with complete remission, but unfortunately died of t-AML harboring t(3;3)(q21;q26).
Assuntos
Cromossomos Humanos Par 3 , Leucemia Mieloide Aguda/induzido quimicamente , Leucemia Mieloide Aguda/genética , Linfoma Difuso de Grandes Células B/genética , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Evolução Fatal , Citometria de Fluxo , Genes bcl-2 , Genes myc , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Cariotipagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Mutação , Translocação GenéticaRESUMO
We have examined the effects of antisense oligonucleotides to bcl-x on the survival and chemosensitivity of CEM cells, a T-acute lymphoblastic leukemia (T-ALL) cell line. Also, we have measured the levels of Bcl-2, Bcl-x, and Bax in 20 cases of T-ALL. By 18 h after the bcl-x antisense treatment, CEM cells showed over a 75% reduction in the levels of Bcl-xL protein and over 30% decreased viable cell counts compared with cells treated with the control oligonucleotide. The combination of bcl-x antisense plus either dexamethasone or doxorubicin showed either strong synergistic or additive killing of CEM cells, respectively. These findings indicate that bcl-x antisense has cytotoxic activity and increases chemotherapy-induced cell death in CEM cells, a model for T-ALL.
Assuntos
Antineoplásicos/farmacologia , Apoptose , Dexametasona/farmacologia , Doxorrubicina/toxicidade , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Oligodesoxirribonucleotídeos Antissenso/toxicidade , Proteínas Proto-Oncogênicas c-bcl-2/genética , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Proto-Oncogênicas/análise , Proteínas Proto-Oncogênicas c-bcl-2/análise , Recidiva , Células Tumorais Cultivadas , Proteína X Associada a bcl-2 , Proteína bcl-XRESUMO
Balanced translocation between chromosomes 3q26 and 8q24 is a very rare event. Here we report six patients with t(3;8)(q26;q24) either as a sole or as a part of genetic abnormalities. Five of the six patients were men with ages ranging from 41 to 84 years old. One patient had a long history of granulocyte colony stimulating factor (G-CSF) treatment. Three of the patients were initially diagnosed with acute myeloid leukemia, two with myelodysplastic syndrome and one with chronic myelogenous leukemia with blast crisis. The peripheral blood in all patients showed severe to moderate anemia; one had absolute neutropenia, one with neutrophilia; four had thrombocytopenia, two with thrombocytosis. The bone marrows from all patients showed dysmegakaryopoiesis with additional erythroid (three patients) and granulocytic (two patients) dysplasia. Cytogenetics revealed t(3;8)(q26;q24) as the sole abnormality in three patients. The majority of patients (4/6) had a poor clinical course, with an average survival of 10 months.
Assuntos
Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 8/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide/genética , Síndromes Mielodisplásicas/genética , Translocação Genética , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Crise Blástica , Evolução Fatal , Feminino , Humanos , Cariótipo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mieloide/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologiaRESUMO
Cell fate can be controlled through asymmetric division and segregation of protein determinants, but the regulation of this process in the hematopoietic system is poorly understood. Here we show that the dynein-binding protein Lis1 is critically required for hematopoietic stem cell function and leukemogenesis. Conditional deletion of Lis1 (also known as Pafah1b1) in the hematopoietic system led to a severe bloodless phenotype, depletion of the stem cell pool and embryonic lethality. Further, real-time imaging revealed that loss of Lis1 caused defects in spindle positioning and inheritance of cell fate determinants, triggering accelerated differentiation. Finally, deletion of Lis1 blocked the propagation of myeloid leukemia and led to a marked improvement in survival, suggesting that Lis1 is also required for oncogenic growth. These data identify a key role for Lis1 in hematopoietic stem cells and mark its directed control of asymmetric division as a critical regulator of normal and malignant hematopoietic development.
Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/fisiologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Leucemia Mieloide/patologia , Leucemia Mieloide/fisiopatologia , Proteínas Associadas aos Microtúbulos/fisiologia , 1-Alquil-2-acetilglicerofosfocolina Esterase/antagonistas & inibidores , 1-Alquil-2-acetilglicerofosfocolina Esterase/deficiência , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Animais , Carcinogênese , Divisão Celular , Linhagem Celular Tumoral , Feminino , Hematopoese , Humanos , Células K562 , Leucemia Mieloide/genética , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/deficiência , Proteínas Associadas aos Microtúbulos/genética , Fenótipo , Gravidez , Fuso Acromático/patologiaRESUMO
A 28-year-old African-American woman presented with new onset of left exophthalmos and diplopia. Computed tomography of the head showed a solitary mass in the left orbit. Excisional biopsy revealed a diffuse infiltrate composed of exclusively λ-restricted monotypic plasma cells based on morphology and immunohistochemistry, consistent with a plasma cell neoplasia. A subsequent staging bone marrow biopsy showed involvement of the bone marrow by λ-restricted monotypic plasma cells, consistent with a plasma cell myeloma. Serum protein electrophoresis and immunofixation studies on the peripheral blood showed a monoclonal band of IgE-λ; thus, an IgE-λ plasma cell myeloma was established. Additional clinical and radiologic workups showed multiple lytic bone lesions, diffuse lymphadenopathy, a pelvic mass, multiple mesenteric soft tissue nodules, and multiple pulmonary nodules, although none of the aforementioned sites was biopsied. The patient was treated with a combination of multiple chemotherapeutic agents and localized radiation due to the aggressive nature of the disease. To the best of our knowledge, this is the first case of an IgE plasma cell myeloma in a patient under the age of 30 years old presenting as a mass in an extramedullary site.
Assuntos
Imunoglobulina E/análise , Mieloma Múltiplo/patologia , Órbita/patologia , Adulto , Feminino , Humanos , Plasmócitos/patologiaRESUMO
ROR1 is a receptor tyrosine kinase expressed during embryogenesis, on chronic lymphocytic leukemia (CLL) and in other malignancies. Hematogones (non-neoplastic B-lymphocyte precursors) express surface ROR1 at an intermediate stage of maturation that lacks CD34 or TdT. The neoplastic counterpart to hematogones is precursor-B acute lymphoblastic leukemia (B-ALL), but less than 10% of B-ALL express surface ROR1, and these ROR1+ B-ALL cases have an unusually high frequency of lacking CD34 and/or having t(1;19), a chromosomal translocation that defines a specific subtype of B-ALL.
Assuntos
Medula Óssea/metabolismo , Leucemia Linfocítica Crônica de Células B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Células Precursoras de Linfócitos B/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase , Antígenos CD/análise , Antígenos CD/biossíntese , Medula Óssea/patologia , Citometria de Fluxo , Regulação da Expressão Gênica no Desenvolvimento , Regulação Neoplásica da Expressão Gênica , Humanos , Imunofenotipagem , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/classificação , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Células Precursoras de Linfócitos B/patologia , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Translocação GenéticaRESUMO
The patient is a 45-year-old woman with a history of breast cancer who had been treated 1 year ago with radiation and chemotherapy. Flow cytometric analysis of bone marrow aspirate revealed 81% blasts positive for CD4, CD11c (partial), CD13, CD19 (partial), cytoplasmic CD22, CD34, CD36, CD45, cytoplasmic CD79a, CD117 (partial), HLA-DR, and terminal deoxynucleotide transferase, consistent with a mixed phenotype acute leukemia (B/myeloid lineage). Conventional karyotypic analysis revealed a t(4;22)(q12;q11.2) in 12 of 13 cells analyzed. Fluorescence in situ hybridization analysis using a dual-color, dual-fusion break cluster region/ABL probe set showed no break cluster region/ABL translocation but an extra break cluster region signal in 85% (170/200) of cells, consistent with a translocation involving the break cluster region gene at 22q11.2. A FIP1L1/CHIC2/platelet-derived growth factor receptor α deletion/fusion probe showed signal separation in 96.5% (193/200) of interphase nuclei. Reverse transcriptase-polymerase chain reaction using sense break cluster region primers and an antisense platelet-derived growth factor receptor α primer resulted in a product of approximately 590 base pairs, consistent with the presence of a break cluster region/platelet-derived growth factor receptor α fusion gene. Because of the presumptive platelet-derived growth factor receptor α translocation and its sensitivity to tyrosine-kinase inhibitor, the patient was treated with imatinib mesylate, cytarabine, and idarubicin as induction and maintenance therapy; and she has remained free of disease for 5 months since the initial diagnosis.
Assuntos
Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 4/genética , Leucemia Aguda Bifenotípica/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Translocação Genética/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas , Quebra Cromossômica , Citarabina/administração & dosagem , Feminino , Citometria de Fluxo , Humanos , Idarubicina/administração & dosagem , Mesilato de Imatinib , Imunofenotipagem , Hibridização in Situ Fluorescente , Cariótipo , Cariotipagem , Leucemia Aguda Bifenotípica/tratamento farmacológico , Pessoa de Meia-Idade , Fenótipo , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Indução de Remissão , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Methods to generate monoclonal antibodies to antigens of neoplastic cells have revolutionized our understanding of cancer cell growth and differentiation, diagnosis, and treatment. Monoclonal antibodies derived by immunizing animals (mostly mice) with mammalian cells or molecules have been critical reagents for the discovery and characterization of many key molecules involved in the behavior of neoplastic cells. Now, over 30 years later, monoclonal antibodies are widely used in the differential diagnosis of cancer and are key elements in the treatment of many forms of cancer. This review will focus on the roles that monoclonal antibodies play in the treatment of hematological malignancies. In particular, we will focus on acute myeloid leukemia and mature B-cell neoplasms.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Animais , Humanos , Leucemia de Células B , Leucemia Mieloide Aguda , Linfoma de Células BRESUMO
Systemic mastocytosis with associated clonal haematological non-mast cell lineage disease (SM-AHNMD) is a heterogeneous group of mast cell disorders with different clinical, pathologic and underlying molecular characteristics. While myelomonocytic/myeloid neoplasia overwhelmingly predominates the AHNMD component, lymphoproliferative disorders rarely occur as an AHNMD component of SM-AHNMD. Here we report two cases of SM-AHNMD, in which the AHNMD component is chronic lymphocytic leukemia in one case, and concurrent chronic lymphocytic leukemia as well as plasma cell myeloma in another case. To the best of our knowledge, this is the first case report of SM-AHNMD with chronic lymphocytic leukemia and plasma cell dyscrasia simultaneously.