المؤلفون: Konopleva M. Y., Dail M., Daver N. G., Garcia J. S., Jonas B. A., Yee K. W. L., Kelly K. R., Vey N., Assouline S., Roboz G. J., Paolini S., Pollyea D. A., Tafuri A., Brandwein J. M., Pigneux A., Powell B. L., Fenaux P., Olin R. L., Visani G., Martinelli G., Onishi M., Wang J., Huang W., Dunshee D. R., Hamidi H., Ott M. G., Hong W. -J., Andreeff M.

المساهمون: Konopleva, M. Y., Dail, M., Daver, N. G., Garcia, J. S., Jonas, B. A., Yee, K. W. L., Kelly, K. R., Vey, N., Assouline, S., Roboz, G. J., Paolini, S., Pollyea, D. A., Tafuri, A., Brandwein, J. M., Pigneux, A., Powell, B. L., Fenaux, P., Olin, R. L., Visani, G., Martinelli, G., Onishi, M., Wang, J., Huang, W., Dunshee, D. R., Hamidi, H., Ott, M. G., Hong, W. -J., Andreeff, M.

مصطلحات موضوعية: B-cell lymphoma-2, Biomarker, Mitogen-activated protein kinase pathway, Targeted therapy

الوصف: Background: Therapies for relapsed/refractory acute myeloid leukemia remain limited and outcomes poor, especially amongst patients who are ineligible for cytotoxic chemotherapy or targeted therapies. Patients and Methods: This phase 1b trial evaluated venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, plus cobimetinib, a MEK1/2 inhibitor, in patients with relapsed/refractory acute myeloid leukemia, ineligible for cytotoxic chemotherapy. Two-dimensional dose-escalation was performed for venetoclax dosed daily, and for cobimetinib dosed on days 1-21 of each 28-day cycle. Results: Thirty patients (median [range] age: 71.5 years [60-84]) received venetoclax-cobimetinib. The most common adverse events (AEs; in ≥40.0% of patients) were diarrhea (80.0%), nausea (60.0%), vomiting (40.0%), febrile neutropenia (40.0%), and fatigue (40.0%). Overall, 66.7% and 23.3% of patients experienced AEs leading to dose modification/interruption or treatment withdrawal, respectively. The composite complete remission (CRc) rate (complete remission [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery) was 15.6%; antileukemic response rate (CRc + morphologic leukemia-free state/partial remission) was 18.8%. For the recommended phase 2 dose (venetoclax: 600 mg; cobimetinib: 40 mg), CRc and antileukemic response rates were both 12.5%. Failure to achieve an antileukemic response was associated with elevated baseline phosphorylated ERK and MCL-1 levels, but not BCL-xL. Baseline mutations in ≥1 signaling gene or TP53 were noted in nonresponders and emerged on treatment. Pharmacodynamic biomarkers revealed inconsistent, transient inhibition of the mitogen-activated protein kinase (MAPK) pathway. Conclusion: Venetoclax-cobimetinib showed limited preliminary efficacy similar to single-agent venetoclax, but with added toxicity. Our findings will inform future trials of BCL-2/MAPK pathway inhibitor combinations.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/38378362; firstpage:1265; lastpage:1276; numberofpages:12; journal:CLINICAL LYMPHOMA MYELOMA & LEUKEMIA; https://hdl.handle.net/11573/1705592Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85185581948

الإتاحة: https://doi.org/10.1016/j.clml.2024.01.007Test
https://hdl.handle.net/11573/1705592Test

المؤلفون: Papaioannou D., Volinia S., Nicolet D., Swierniak M., Petri A., Mrozek K., Bill M., Pepe F., Walker C. J., Walker A. E., Carroll A. J., Kohlschmidt J., Eisfeld A. -K., Powell B. L., Uy G. L., Kolitz J. E., Wang E. S., Kauppinen S., Dorrance A., Stone R. M., Byrd J. C., Bloomfield C. D., Garzon R.

المساهمون: Papaioannou, D., Volinia, S., Nicolet, D., Swierniak, M., Petri, A., Mrozek, K., Bill, M., Pepe, F., Walker, C. J., Walker, A. E., Carroll, A. J., Kohlschmidt, J., Eisfeld, A. -K., Powell, B. L., Uy, G. L., Kolitz, J. E., Wang, E. S., Kauppinen, S., Dorrance, A., Stone, R. M., Byrd, J. C., Bloomfield, C. D., Garzon, R.

الوصف: Circular RNAs (circRNAs) are noncoding RNA molecules that display a perturbed arrangement of exons, called backsplicing. To examine the prognostic and biologic significance of circRNA expression in cytogenetically normal acute myeloid leukemia (CN-AML), we conducted whole-transcriptome profiling in 365 younger adults (age 18- 60 years) with CN-AML. We applied a novel pipeline, called Massive Scan for circRNA, to identify and quantify circRNA expression. We validated the high sensitivity and specificity of our pipeline by performing RNase R treatment and RNA sequencing in samples of AML patients and cell lines. Unsupervised clustering analyses identified 3 distinct circRNA expression-based clusters with different frequencies of clinical and molecular features. After dividing our cohort into training and validation data sets, we identified 4 circRNAs (circCFLAR, circKLHL8, circSMC1A, and circFCHO2) that were prognostic in both data sets; high expression of each prognostic circRNA was associated with longer disease-free, overall, and event-free survival. In multivariable analyses, high circKLHL8 and high circFCHO2 expression were independently associated with better clinical outcome of CN-AML patients, after adjusting for other covariates. To examine the biologic relevance of circRNA expression, we performed knockdown screening experiments in a subset of prognostic and gene mutation-related candidate circRNAs. We identified circFBXW7, but not its linear messenger RNA, as a regulator of the proliferative capacity of AML blasts. In summary, our findings underscore the molecular associations, prognostic significance, and functional relevance of circRNA expression in CN-AML.

وصف الملف: STAMPA

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/31945158; info:eu-repo/semantics/altIdentifier/wos/WOS:000510001000001; volume:4; issue:2; firstpage:239; lastpage:251; numberofpages:13; journal:BLOOD ADVANCES; http://hdl.handle.net/11392/2433812Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85082115069; https://doi.org/10.1182/bloodadvances.2019000568Test; https://ashpublications.org/bloodadvances/article/4/2/239/431019/Clinical-and-functional-significance-of-circularTest

الإتاحة: https://doi.org/10.1182/bloodadvances.2019000568Test
http://hdl.handle.net/11392/2433812Test
https://ashpublications.org/bloodadvances/article/4/2/239/431019/Clinical-and-functional-significance-of-circularTest

المؤلفون: Ngankeu A., Ranganathan P., Havelange V., Nicolet D., Volinia S., Powell B. L., Kolitz J. E., Uy G. L., Stone R. M., Kornblau S. M., Andreeff M., Croce C. M., Bloomfield C. D., Garzon R.

المساهمون: Ngankeu, A., Ranganathan, P., Havelange, V., Nicolet, D., Volinia, S., Powell, B. L., Kolitz, J. E., Uy, G. L., Stone, R. M., Kornblau, S. M., Andreeff, M., Croce, C. M., Bloomfield, C. D., Garzon, R.

مصطلحات موضوعية: AML, miR-29b-1/miR-29a cluster, Polymorphism

الوصف: We previously reported that microRNA (miR)-29b is down-regulated and has a tumor suppressor role in acute myeloid leukemia (AML). However, little is known about the mechanisms responsible for miR-29b expression downregulation in AML. In this work we screened for mutations that could affect miR-29b expression. Using Sanger sequencing, we identified a germline thymidine (T) base deletion within the miR-29b-1/miR-29a cluster precursor in 16% of AML patients. Remarkably we found a significant enrichment for the presence of the miR-29 polymorphism in core binding factor (CBF) newly diagnosed AML patients (n = 61/303; 20%) with respect to age, sex and race matched controls (n = 43/402:11%, P < 0.01). Mechanistically, this polymorphism affects the expression ratio of mature miR-29b and miR-29a by dampening the processing of miR-29a. RNA immunoprecipitation assays showed reduced DROSHA binding capacity to the polymorphism with respect to the controls. Finally, we showed that this polymorphism negatively impacts the ability of miR- 29b-1/miR-29a cluster to target MCL-1 and CDK6, both known miR-29 targets.

وصف الملف: ELETTRONICO

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/29435107; info:eu-repo/semantics/altIdentifier/wos/WOS:000422651700007; volume:9; issue:4; firstpage:4354; lastpage:4365; numberofpages:12; journal:ONCOTARGET; http://hdl.handle.net/11392/2418529Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85040440786; https://www.oncotarget.com/article/23150/textTest/

الإتاحة: https://doi.org/10.18632/oncotarget.23150Test
http://hdl.handle.net/11392/2418529Test
https://www.oncotarget.com/article/23150/textTest/

المؤلفون: Niederwieser, C, Kohlschmidt, J., VOLINIA, Stefano, Whitman, S. P., Metzeler, K. H., Eisfeld, A. K., Maharry, K., Yan, P., Frankhouser, D., Becker, H., Schwind, S., Carroll, A. J., Nicolet, D., Mendler, J. H., Curfman, J. P., Wu, Y. Z., Baer, M. R., Powell, B. L., Kolitz, J. E., Moore, J. O., Carter, T. H., Bundschuh, R., Larson, R. A., Stone, R. M., Mrózek, K., Marcucci, G., Bloomfield, C. D.

المساهمون: Niederwieser, C, Kohlschmidt, J., Volinia, Stefano, Whitman, S. P., Metzeler, K. H., Eisfeld, A. K., Maharry, K., Yan, P., Frankhouser, D., Becker, H., Schwind, S., Carroll, A. J., Nicolet, D., Mendler, J. H., Curfman, J. P., Wu, Y. Z., Baer, M. R., Powell, B. L., Kolitz, J. E., Moore, J. O., Carter, T. H., Bundschuh, R., Larson, R. A., Stone, R. M., Mrózek, K., Marcucci, G., Bloomfield, C. D.

مصطلحات موضوعية: noAge Factor, Aged, 80 and over, Cytarabine, DNA (Cytosine-5-)-Methyltransferase, DNA Methylation, Daunorubicin, Female, Gene Expression Profiling, Human, Induction Chemotherapy, Karyotyping, Leukemia, Myeloid, Acute, Male, MicroRNA, Microarray Analysi, Middle Aged, Prognosi, Survival Analysi, Gene Expression Regulation, Leukemic

الوصف: DNMT3B encodes a DNA methyltransferase implicated in aberrant epigenetic changes contributing to leukemogenesis. We tested whether DNMT3B expression, measured by NanoString nCounter assay, associates with outcome, gene and microRNA expression and DNA methylation profiles in 210 older (≥60 years) adults with primary, cytogenetically normal acute myeloid leukemia (CN-AML). Patients were dichotomized into high versus low expressers using median cut. Outcomes were assessed in the context of known CN-AML prognosticators. Gene and microRNA expression, and DNA methylation profiles were analyzed using microarrays and MethylCap-sequencing, respectively. High DNMT3B expressers had fewer complete remissions (CR; P=0.002) and shorter disease-free (DFS; P=0.02) and overall (OS; P<0.001) survival. In multivariable analyses, high DNMT3B expression remained an independent predictor of lower CR rates (P=0.04) and shorter DFS (P=0.04) and OS (P=0.001). High DNMT3B expression associated with a gene expression profile comprising 363 genes involved in differentiation, proliferation and survival pathways, but with only four differentially expressed microRNAs (miR-133b, miR-148a, miR-122, miR-409-3p) and no differential DNA methylation regions. We conclude that high DNMT3B expression independently associates with adverse outcome in older CN-AML patients. Gene expression analyses suggest that DNMT3B is involved in the modulation of several genes, although the regulatory mechanisms remain to be investigated to devise therapeutic approaches specific for these patients.

وصف الملف: STAMPA

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/25204569; info:eu-repo/semantics/altIdentifier/wos/WOS:000350734300006; volume:29; issue:3; firstpage:567; lastpage:575; numberofpages:9; journal:LEUKEMIA; http://hdl.handle.net/11392/2356328Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-84924599811; https://www.nature.com/articles/leu2014267Test

الإتاحة: https://doi.org/10.1038/leu.2014.267Test
http://hdl.handle.net/11392/2356328Test
https://www.nature.com/articles/leu2014267Test

المؤلفون: Madan V., Shyamsunder P., Han L., Mayakonda A., Nagata Y., Sundaresan J., Kanojia D., Yoshida K., Ganesan S., Hattori N., Fulton N., Tan K. -T., Alpermann T., Kuo M. -C., Rostami S., Matthews J., Sanada M., Liu L. -Z., Shiraishi Y., Miyano S., Chendamarai E., Hou H. -A., Malnassy G., Ma T., Garg M., Ding L. -W., Sun Q. -Y., Chien W., Ikezoe T., Lill M., Biondi A., Larson R. A., Powell B. L., Lubbert M., Chng W. J., Tien H. -F., Heuser M., Ganser A., Koren-Michowitz M., Kornblau S. M., Kantarjian H. M., Nowak D., Hofmann W. -K., Yang H., Stock W., Ghavamzadeh A., Alimoghaddam K., Haferlach T., Ogawa S., Shih L. -Y., Mathews V., Koeffler H. P.

المساهمون: Madan, V, Shyamsunder, P, Han, L, Mayakonda, A, Nagata, Y, Sundaresan, J, Kanojia, D, Yoshida, K, Ganesan, S, Hattori, N, Fulton, N, Tan, K, Alpermann, T, Kuo, M, Rostami, S, Matthews, J, Sanada, M, Liu, L, Shiraishi, Y, Miyano, S, Chendamarai, E, Hou, H, Malnassy, G, Ma, T, Garg, M, Ding, L, Sun, Q, Chien, W, Ikezoe, T, Lill, M, Biondi, A, Larson, R, Powell, B, Lubbert, M, Chng, W, Tien, H, Heuser, M, Ganser, A, Koren-Michowitz, M, Kornblau, S, Kantarjian, H, Nowak, D, Hofmann, W, Yang, H, Stock, W, Ghavamzadeh, A, Alimoghaddam, K, Haferlach, T, Ogawa, S, Shih, L, Mathews, V, Koeffler, H

مصطلحات موضوعية: Cell Differentiation, DNA Mutational Analysi, DNA-Binding Protein, Exome, Gene Expression Profiling, Human, Leukemia, Promyelocytic, Acute, Nuclear Protein, Recurrence, Transcription Factors

الوصف: Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/27063598; info:eu-repo/semantics/altIdentifier/wos/WOS:000380826400005; volume:30; issue:8; firstpage:1672; lastpage:1681; numberofpages:10; journal:LEUKEMIA; http://hdl.handle.net/10281/259208Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-84965079020; http://www.nature.com/leu/index.htmlTest

الإتاحة: https://doi.org/10.1038/leu.2016.69Test
http://hdl.handle.net/10281/259208Test
http://www.nature.com/leu/index.htmlTest

المؤلفون: Madan, V, Shyamsunder, P, Han, L, Mayakonda, A, Nagata, Y, Sundaresan, J, Kanojia, D, Yoshida, K, Ganesan, S, Hattori, N, Fulton, N, Tan, K T, Alpermann, T, Kuo, M C, Rostami, S, Matthews, J, Sanada, M, Liu, L-Z, Shiraishi, Y, Miyano, S, Chendamarai, E, Hou, H A, Malnassy, G, Ma, T, Garg, M, Ding, L W, Sun, Q Y, Chien, W, Ikezoe, T, Lill, M, Biondi, A, Larson, R A, Powell, B L, Lübbert, M, Chng, W J, Tien, H F, Heuser, M, Ganser, A, Koren-Michowitz, M, Kornblau, S M, Kantarjian, H M, Nowak, D, Hofmann, W K, Yang, H, Stock, W, Ghavamzadeh, A, Alimoghaddam, K, Haferlach, T, Ogawa, S, Shih, L Y

المصدر: Leukemia ; volume 30, issue 12, page 2430-2430 ; ISSN 0887-6924 1476-5551

مصطلحات موضوعية: Oncology, Cancer Research, Hematology

الإتاحة: https://doi.org/10.1038/leu.2016.237Test
https://www.nature.com/articles/leu2016237.pdfTest
https://www.nature.com/articles/leu2016237Test

المؤلفون: Niederwieser, C, Kohlschmidt, J, Volinia, S, Whitman, S P, Metzeler, K H, Eisfeld, A-K, Maharry, K, Yan, P, Frankhouser, D, Becker, H, Schwind, S, Carroll, A J, Nicolet, D, Mendler, J H, Curfman, J P, Wu, Y-Z, Baer, M R, Powell, B L, Kolitz, J E, Moore, J O, Carter, T H, Bundschuh, R, Larson, R A, Stone, R M, Mrózek, K, Marcucci, G, Bloomfield, C D

المصدر: Leukemia ; volume 29, issue 3, page 567-575 ; ISSN 0887-6924 1476-5551

مصطلحات موضوعية: Oncology, Cancer Research, Hematology

الإتاحة: https://doi.org/10.1038/leu.2014.267Test
https://www.nature.com/articles/leu2014267.pdfTest
https://www.nature.com/articles/leu2014267Test

المؤلفون: Powell, B. L.

المصدر: Journal of Animal Ecology, 1962 Jun 01. 31(2), 251-261.

الوصول الحر: https://www.jstor.org/stable/2139Test

المؤلفون: Metzeler, K H, Maharry, K, Kohlschmidt, J, Volinia, S, Mrózek, K, Becker, H, Nicolet, D, Whitman, S P, Mendler, J H, Schwind, S, Eisfeld, A-K, Wu, Y-Z, Powell, B L, Carter, T H, Wetzler, M, Kolitz, J E, Baer, M R, Carroll, A J, Stone, R M, Caligiuri, M A, Marcucci, G, Bloomfield, C D

المصدر: Leukemia ; volume 27, issue 10, page 2023-2031 ; ISSN 0887-6924 1476-5551

مصطلحات موضوعية: Oncology, Cancer Research, Hematology

الإتاحة: https://doi.org/10.1038/leu.2013.181Test
https://www.nature.com/articles/leu2013181.pdfTest
https://www.nature.com/articles/leu2013181Test

المؤلفون: Whitman, S P, Caligiuri, M A, Maharry, K, Radmacher, M D, Kohlschmidt, J, Becker, H, Mrózek, K, Wu, Y-Z, Schwind, S, Metzeler, K H, Mendler, J H, Wen, J, Baer, M R, Powell, B L, Carter, T H, Kolitz, J E, Wetzler, M, Carroll, A J, Larson, R A, Marcucci, G, Bloomfield, C D

المصدر: Leukemia ; volume 26, issue 7, page 1713-1717 ; ISSN 0887-6924 1476-5551

مصطلحات موضوعية: Oncology, Cancer Research, Hematology

الإتاحة: https://doi.org/10.1038/leu.2012.34Test
https://www.nature.com/articles/leu201234.pdfTest
https://www.nature.com/articles/leu201234Test