Identification of Bruton's tyrosine kinase as a therapeutic target in acute myeloid leukemia

Bruton's tyrosine kinase (BTK) is a cytoplasmic protein found in all hematopoietic cell lineages except for T cells. BTK mediates signalling downstream of a number of receptors. Pharmacological targeting of BTK using ibrutinib (previously PCI-32765) has recently shown encouraging clinical activity in a range of lymphoid malignancies. This study reports for the first time that ibrutinib inhibits blast proliferation from human acute myeloid leukaemia (AML) and that treatment with ibrutinib significantly augmented cytotoxic activities of standard AML chemotherapy cytarabine or daunorubicin. Here we describe that BTK is constitutively phosphorylated in the majority of AML samples tested, with BTK phosphorylation correlating highly with the cell's cytotoxic sensitivity towards ibrutinib. BTK targeted RNAi knock-down reduced colony forming capacity of primary AML blasts and proliferation of AML cell lines. We showed ibrutinib binds at nanomolar range to BTK. Furthermore, we also showed ibrutinib's anti-proliferative effects in AML are mediated via an inhibitory effect on downstream nuclear factor-κB (NF-κB) survival pathways. Moreover, ibrutinib inhibited AML cell adhesion to bone marrow stroma. Furthermore, these effects of ibrutinib in AML were seen at comparable concentrations efficacious in chronic lymphocytic leukemia (CLL). These results provide a biologic rationale for clinical evaluation of BTK inhibition in AML patients

Activity of Bruton's tyrosine-kinase inhibitor ibrutinib in patients with CD117-positive acute myeloid leukaemia: a mechanistic study using patient-derived blast cells

Background: Roughly 80% of patients with acute myeloid leukaemia have high activity of Bruton's tyrosine-kinase (BTK) in their blast cells compared with normal haemopoietic cells, rendering the cells sensitive to the oral BTK inhibitor ibrutinib in vitro. We aimed to develop the biological understanding of the BTK pathway in acute myeloid leukaemia to identify clinically relevant diagnostic information that might define a subset of patients that should respond to ibrutinib treatment. Methods: We obtained acute myeloid leukaemia blast cells from unselected patients attending our UK hospital between Feb 19, 2010, and Jan 20, 2014. We isolated primary acute myeloid leukaemia blast cells from heparinised blood and human peripheral blood mononuclear cells to establish the activity of BTK in response to CD117 activation. Furthermore, we investigated the effects of ibrutinib on CD117-induced BTK activation, downstream signalling, adhesion to primary bone-marrow mesenchymal stromal cells, and proliferation of primary acute myeloid leukaemia blast cells. We used the Mann-Whitney U test to compare results between groups. Findings: We obtained acute myeloid leukaemia blast cells from 29 patients. Ibrutinib significantly inhibited CD117-mediated proliferation of primary acute myeloid leukaemia blast cells (p=0·028). CD117 activation increased BTK activity by inducing phosphorylated BTK in patients with CD117-positive acute myeloid leukaemia. Furthermore, ibrutinib inhibited CD117-induced activity of BTK and downstream kinases at a concentration of 100 nM or more. CD117-mediated adhesion of CD117-expressing blast cells to bone-marrow stromal cells was significantly inhibited by Ibrutinib at 500 nM (p=0·028) Interpretation: As first-in-man clinical trials of ibrutinib in patients with acute myeloid leukaemia commence, the data suggest not all patients will respond. Our findings show that BTK has specific pro-tumoural biological actions downstream of surface CD117 activation, which are inhibited by ibrutinib. Accordingly, we propose that patients with acute myeloid leukaemia whose blast cells express CD117 should be considered for forthcoming clinical trials of ibrutinib

Molecular map of chronic lymphocytic leukemia and its impact on outcome

Recent advances in cancer characterization have consistently revealed marked heterogeneity, impeding the completion of integrated molecular and clinical maps for each malignancy. Here, we focus on chronic lymphocytic leukemia (CLL), a B cell neoplasm with variable natural history that is conventionally categorized into two subtypes distinguished by extent of somatic mutations in the heavy-chain variable region of immunoglobulin genes (IGHV). To build the ‘CLL map,’ we integrated genomic, transcriptomic and epigenomic data from 1,148 patients. We identified 202 candidate genetic drivers of CLL (109 new) and refined the characterization of IGHV subtypes, which revealed distinct genomic landscapes and leukemogenic trajectories. Discovery of new gene expression subtypes further subcategorized this neoplasm and proved to be independent prognostic factors. Clinical outcomes were associated with a combination of genetic, epigenetic and gene expression features, further advancing our prognostic paradigm. Overall, this work reveals fresh insights into CLL oncogenesis and prognostication

The PI3-kinase delta inhibitor idelalisib (GS-1101) targets integrin-mediated adhesion of chronic lymphocytic leukemia (CLL) cell to endothelial and marrow stromal cells

CLL cell trafficking between blood and tissue compartments is an integral part of the disease process. Idelalisib, a phosphoinositide 3-kinase delta (PI3K\u3b4) inhibitor causes rapid lymph node shrinkage, along with an increase in lymphocytosis, prior to inducing objective responses in CLL patients. This characteristic activity presumably is due to CLL cell redistribution from tissues into the blood, but the underlying mechanisms are not fully understood. We therefore analyzed idelalisib effects on CLL cell adhesion to endothelial and bone marrow stromal cells (EC, BMSC). We found that idelalisib inhibited CLL cell adhesion to EC and BMSC under static and shear flow conditions. TNF\u3b1-induced VCAM-1 (CD106) expression in supporting layers increased CLL cell adhesion and accentuated the inhibitory effect of idelalisib. Co-culture with EC and BMSC also protected CLL from undergoing apoptosis, and this EC- and BMSC-mediated protection was antagonized by idelalisib. Furthermore, we demonstrate that CLL cell adhesion to EC and VLA-4 (CD49d) resulted in the phosphorylation of Akt, which was sensitive to inhibition by idelalisib. These findings demonstrate that idelalisib interferes with integrin-mediated CLL cell adhesion to EC and BMSC, providing a novel mechanism to explain idelalisib-induced redistribution of CLL cells from tissues into the blood

PI3K Signaling in Normal B Cells and Chronic Lymphocytic Leukemia (CLL).

B cells provide immunity to extracellular pathogens by secreting a diverse repertoire of antibodies with high affinity and specificity for exposed antigens. The B cell receptor (BCR) is a transmembrane antibody, which facilitates the clonal selection of B cells producing secreted antibodies of the same specificity. The diverse antibody repertoire is generated by V(D)J recombination of heavy and light chain genes, whereas affinity maturation is mediated by activation-induced cytidine deaminase (AID)-mediated mutagenesis. These processes, which are essential for the generation of adaptive humoral immunity, also render B cells susceptible to chromosomal rearrangements and point mutations that in some cases lead to cancer. In this chapter, we will review the central role of PI3K s in mediating signals from the B cell receptor that not only facilitate the development of functional B cell repertoire, but also support the growth and survival of neoplastic B cells, focusing on chronic lymphocytic leukemia (CLL) B cells. Perhaps because of the central role played by PI3K in BCR signaling, B cell leukemia and lymphomas are the first diseases for which a PI3K inhibitor has been approved for clinical use

La reforma del poder judicial: en busca de un camino estructural

Me han preguntado varias veces: ¿está usted por la reforma o por el cambio estructural? Yo pienso más en cambio estructural que en reforma; reforma suena a fracaso. Además ahora se está usando mucho esa palabra en los niveles políticos y en todos los niveles del Estado

Estilo motivacional docente y aprendizaje del inglés en estudiantes de secundaria

La presente investigación se planteó como objetivo el estudiar la relación entre el estilo motivacional docente, las metas de logro de aproximación al dominio y al desempeño y evitación del desempeño, las razones controladas detrás de las metas de aproximación, las estrategias de evitación y el rendimiento académico en el aprendizaje del inglés. La muestra estuvo compuesta por 479 estudiantes de secundaria de dos colegios privados y mixtos del Callao. Se llevaron a cabo análisis de regresiones lineales para evaluar tres modelos específicos correspondientes a las hipótesis de las relaciones predictivas entre las variables. En primer lugar, se encontró que la estrategia de autosabotaje académico era predicho positivamente por el estilo motivacional de control docente y las metas de aproximación al dominio por razones controladas, y de forma negativa por las metas de aproximación al dominio. En segundo lugar, se observó que la estrategia de evitación de la novedad era predicha de manera positiva por el estilo de control docente y de manera negativa por las metas de aproximación al dominio. En ambos casos, las metas de aproximación al dominio resultaron ser las variables predictoras más fuertes. En tercer lugar, se halló que el rendimiento sólo era predicho por las metas de aproximación al dominio. Por último, se identificaron diferencias de acuerdo al sexo de los participantes, las cuales serán pertinentes de evaluar en futuras líneas de investigación. Asimismo, se recomienda estudiar qué otras variables median la relación entre el estilo motivacional docente y el uso de estrategias de evitación.The aim of the present study was to study the relationship between teacher’s motivational style, mastery and performance approach goals, performance avoidance goals, the controlled reasons behind the approach goals, avoidance strategies and academic achievement in English learning. The sample consisted of 479 secondary students from two private schools in Callao. Linear regression analyzes were carried out to determine whether the three predictive models hypothesized took place. In first place, self-handicapping was predicted positively by the controlling teacher’s style and the controlled reasons for mastery approach goals, and negatively by the mastery approach goals. In second place, avoidance of novelty was positively predicted by the controlling teacher’s style and negatively by mastery approach goals. In both cases, approach goals were the strongest predictors. In third place, only approach goals were significant predictors of academic achievement in English learning. Finally, there were significant differences found according to the participant’s sex that should be taken into account in future lines of work. Moreover, other studies should examine other variables that mediate the relationship between teacher’s motivational style and the use of avoidance strategies

Analisis Kesulitan Membaca Permulaan Siswa Kelas I Sekolah Dasar

Tujuan dari penelitian ini adalah untuk mendeskripsikan kesulitan membaca permulaan dalam membaca nyaring siswa kelas I di Sekolah Dasar. Penelitian ini dilakukan di Sekolah Dasar Negeri Nomor 186/I Sridadi pada bulan Maret 2022. Data penelitian diperoleh dengan cara melakukan observasi, wawancara dan dokumentasi. Pengumpulan data bertujuan untuk melihat kesulitan membaca permulaan dalam membaca nyaring siswa kelas I Sekolah Dasar. Pendekatan pada penelitian ini menggunakan pendekatan kualitatif dengan jenis penelitian studi kasus. Adapun subjek penelitian ini adalah guru kelas I dan siswa kelas I SD Negeri 186/I Sridadi dan orang tua murid. Data yang diperoleh kemudian dianalisis dengan tahapan pertama reduksi data, tahapan kedua penyajian data, dan tahapan ketiga verifikasi data. Hasil penelitian menunjukkan bagaimana kesulitan membaca permulaan dalam membaca nyaring siswa kelas I sekolah dasar. Siswa kelas I Sekolah Dasar Negeri 186/I Sridadi mengalami kesulitan dalam membaca nyaring. Kesulitan yang dialami siswa yaitu kesulitan dalam mengenal huruf, kesulitan membaca suku kata, kesulitan membaca kata, kesulitan membaca kalimat sederhana, dan kesulitan membaca dengan lafal dan intonasi yang jelas. Kesulitan membaca permulaan dalam teknik membaca nyaring tersebut masih dialami oleh siswa kelas I SDN 186/I Sridadi