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1. Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia

Author

Swaminathan, S, Klemm, L, Park, E, Papaemmanuil, E, Ford, A, Kweon, SM, Trageser, D, Hasselfeld, B, Henke, N, Mooster, J, Geng, H, Schwarz, K, Kogan, SC, Casellas, R, Schatz, DG, Lieber, MR, Greaves, MF, and Müschen, M

Subjects
Immunology
Abstract

Childhood acute lymphoblastic leukemia (ALL) can often be traced to a pre-leukemic clone carrying a prenatal genetic lesion. Postnatally acquired mutations then drive clonal evolution toward overt leukemia. The enzymes RAG1-RAG2 and AID, which diversify immunoglobulin-encoding genes, are strictly segregated in developing cells during B lymphopoiesis and peripheral mature B cells, respectively. Here we identified small pre-BII cells as a natural subset with increased genetic vulnerability owing to concurrent activation of these enzymes. Consistent with epidemiological findings on childhood ALL etiology, susceptibility to genetic lesions during B lymphopoiesis at the transition from the large pre-BII cell stage to the small pre-BII cell stage was exacerbated by abnormal cytokine signaling and repetitive inflammatory stimuli. We demonstrated that AID and RAG1-RAG2 drove leukemic clonal evolution with repeated exposure to inflammatory stimuli, paralleling chronic infections in childhood.

Published
2015

2. Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia

Author

Shojaee, S, Caeser, R, Buchner, M, Park, E, Swaminathan, S, Hurtz, C, Geng, H, Chan, LN, Klemm, L, Hofmann, WK, Qiu, YH, Zhang, N, Coombes, KR, Paietta, E, Molkentin, J, Koeffler, HP, Willman, CL, Hunger, SP, Melnick, A, Kornblau, SM, and Müschen, M

Subjects
Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Studying mechanisms of malignant transformation of human pre-B cells, we found that acute activation ofoncogenes induced immediate cell death in the vast majority of cells. Few surviving pre-B cell clones had acquired permissiveness to oncogenic signaling by strong activation of negative feedback regulation ofErk signaling. Studying negative feedback regulation of Erk in genetic experiments at three different levels,we found that Spry2, Dusp6, and Etv5 were essential for oncogenic transformation in mouse modelsfor pre-B acute lymphoblastic leukemia (ALL). Interestingly, a small molecule inhibitor of DUSP6 selectively induced cell death in patient-derived pre-B ALL cells and overcame conventional mechanisms of drug-resistance. Shojaee etal. show that successful transformation of pre-B cells to pre-B acute lymphoblastic leukemia (ALL) requires negative feedback regulation of Erk signaling and inhibiting this feedback selectively kills pre-B ALL cells, suggesting negative feedback regulation of oncogenes as a vulnerability in human ALL.

Published
2015

3. Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia

Author

Kogan, Scott, Muschen, Markus, Swaminathan, S, Klemm, L, Park, E, Papaemmanuil, E, Ford, A, Kweon, SM, Trageser, D, Hasselfeld, B, Henke, N, and Mooster, J

Abstract

© 2015 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Childhood acute lymphoblastic leukemia (ALL) can often be traced to a pre-leukemic clone carrying a prenatal genetic lesion. Postnatally acquired mutations the

Published
2015

4. Identification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia

Author

Muschen, Markus, Buchner, M, Park, E, Geng, H, Klemm, L, Flach, J, Passegué, E, Schjerven, H, Melnick, A, Paietta, E, and Kopanja, D

Abstract

© 2015 Macmillan Publishers Limited.Despite recent advances in the cure rate of acute lymphoblastic leukaemia (ALL), the prognosis for patients with relapsed ALL remains poor. Here we identify FOXM1 as a candidate responsible for an aggressive clinical cou

Published
2015

5. Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia

Author

Muschen, Markus, Gang, EJ, Hsieh, YT, Pham, J, Zhao, Y, Nguyen, C, Huantes, S, Park, E, Naing, K, Klemm, L, and Swaminathan, S

Abstract

Drug resistance in acute lymphoblastic leukemia (ALL) remains a major problem warranting new treatment strategies. Wnt/catenin signaling is critical for the self-renewal of normal hematopoietic progenitor cells. Deregulated Wnt signaling is evident in chro

Published
2014

6. AID downregulation is a novel function of the DNMT inhibitor 5-aza-deoxycytidine

Author

Muschen, Markus, Tsai, CT, Yang, PM, Chern, TR, Chuang, SH, Lin, JH, Klemm, L, Müschen, M, and Chen, CC

Abstract

Activation-induced cytidine deaminase (AID) was originally identified as an inducer of somatic hypermutation (SHM) and class switch recombination (CSR) in immunoglobulin genes. However, AID can also cause mutations in host genes and contribute to cancer pr

Published
2014

7. Consistently combined Earth Orientation Parameters as an operational product

Author

Klemm, L., Thaller, D., Flohrer, C., Walenta, A., Ullrich, D., and Hellmers, H.

Abstract

We present BKG´s current activities in the area of combined data processing of different space-geodetic techniques. The primary goal of the combined analyses is the improvement of the consistency between the techniques through common parameters, mainly Earth Orientation Parameters (EOP), and thereby to improve also the resulting EOP. In previous studies, we have investigated different combination approaches using VLBI and GNSS data. We generate EOP series with latencies of about 1 to 14 days, depending on the input data we used. In this way, a significant improvement in accuracy compared to the individual technique-specific solutions was achieved, especially for the highly variable dUT1. The processing is based on homogenized datum-free normal equations, which allow a rigorous combination on the normal equation level.Our main objective is to generate a continuous, daily and regular EOP product with the shortest possible latency, especially for the parameter dUT1. The requirement for achieving these goals is the daily and rapid availability of the input data. Especially the VLBI Intensive sessions play an important role for the precise and rapid estimation of dUT1. In the last two years, an increasing number of VGOS Intensive campaigns has been conducted in addition to the legacy Intensives. In our recent studies, we integrate the new data into our combination process to improve the continuity and regularity of our EOP series.Based on the improved combination method, we intent to establish an operational EOP product at BKG. We present our future plans regarding the generation and availability of the new product., The 28th IUGG General Assembly (IUGG2023) (Berlin 2023)

Published
2023
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9. Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer

Author

Sadras, T, Martin, M, Kume, K, Robinson, ME, Saravanakumar, S, Lenz, G, Chen, Z, Song, JY, Siddiqi, T, Oksa, L, Knapp, AM, Cutler, J, Cosgun, KN, Klemm, L, Ecker, V, Winchester, J, Ghergus, D, Soulas-Sprauel, P, Kiefer, F, Heisterkamp, N, Pandey, A, Ngo, V, Wang, L, Jumaa, H, Buchner, M, Ruland, J, Chan, W-C, Meffre, E, Martin, T, Muschen, M, Sadras, T, Martin, M, Kume, K, Robinson, ME, Saravanakumar, S, Lenz, G, Chen, Z, Song, JY, Siddiqi, T, Oksa, L, Knapp, AM, Cutler, J, Cosgun, KN, Klemm, L, Ecker, V, Winchester, J, Ghergus, D, Soulas-Sprauel, P, Kiefer, F, Heisterkamp, N, Pandey, A, Ngo, V, Wang, L, Jumaa, H, Buchner, M, Ruland, J, Chan, W-C, Meffre, E, Martin, T, and Muschen, M

Abstract

Even though SYK and ZAP70 kinases share high sequence homology and serve analogous functions, their expression in B and T cells is strictly segregated throughout evolution. Here, we identified aberrant ZAP70 expression as a common feature in a broad range of B cell malignancies. We validated SYK as the kinase that sets the thresholds for negative selection of autoreactive and premalignant clones. When aberrantly expressed in B cells, ZAP70 competes with SYK at the BCR signalosome and redirects SYK from negative selection to tonic PI3K signaling, thereby promoting B cell survival. In genetic mouse models for B-ALL and B-CLL, conditional expression of Zap70 accelerated disease onset, while genetic deletion impaired malignant transformation. Inducible activation of Zap70 during B cell development compromised negative selection of autoreactive B cells, resulting in pervasive autoantibody production. Strict segregation of the two kinases is critical for normal B cell selection and represents a central safeguard against the development of autoimmune disease and B cell malignancies.

Published
2021

17. Online Guideline Development

Author

Klemm, L, Wohlfarth, E, Karge, T, and Fitzke, K

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

‚Clinical Practice Guidelines’ play an important role in daily work to support the decision of medical treatment. The quality and medical value of guidelines depend on a systematic and transparent development methodology. The 4 different guideline classifications in Germany have their [for full text, please go to the a.m. URL], Prävention zwischen Evidenz und Eminenz; 15. Jahrestagung des Deutschen Netzwerks Evidenzbasierte Medizin

Published
2014
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19. Mikrochemie

Author

Klein, G., Pollauf, Gertrud, Krisch, Marie, Farkass, Elisabeth, Schusta, F., Niethammer, Anneliese, Lander, G. D., Glycart, C. K., Wagenaar, M., Pavelka, F., van Itallie, L., Steenhauer, A. J., van der Veen, A. L. W. E., Denigès, G., Rosenthaler, L., Krüger, D., Tschirch, E., Tangl, H., Fischer, R., Stauder, F., Dangl, F., Kofler, L., Hilbck, H., Griebel, C., Weiß, F., Hinrichs, A., Klemm, L., Mohr, O., Alber, H., Gläser, M., Morawski, Th., and Rose, J. A.

Published
1933
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21. Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia

Author

Gang, E J, primary, Hsieh, Y-T, additional, Pham, J, additional, Zhao, Y, additional, Nguyen, C, additional, Huantes, S, additional, Park, E, additional, Naing, K, additional, Klemm, L, additional, Swaminathan, S, additional, Conway, E M, additional, Pelus, L M, additional, Crispino, J, additional, Mullighan, C G, additional, McMillan, M, additional, Müschen, M, additional, Kahn, M, additional, and Kim, Y-M, additional

Published
2013
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22. Educational topics of the day. Chips from a teacher's workshop, by L.R. Klemm.

Author

Klemm, L. R., Klemm, L.R. (Louis Richard), 1845-1925., Klemm, L. R., and Klemm, L.R. (Louis Richard), 1845-1925.

Abstract

We have determined this item to be in the public domain according to US copyright law through information in the bibliographic record and/or US copyright renewal records. The digital version is available for all educational uses worldwide. Please contact HathiTrust staff at hathitrust-help@umich.edu with any questions about this item., Teaching., (LCCN)06030625., (OCoLC)5197876., Sdr-nrlfGLAD236310-B., Sdr-ia-srlf1889405., LB1025 .K58., Http://hdl.handle.net/2027/uc1.b262260., Http://hdl.handle.net/2027/uc2.ark:/13960/t0ks6w24v.

Published
1888

23. Poesie für Haus und Schule. A collection of German poems for use in schools and families. Selected and arranged by L.R. Klemm.

Author

Klemm, L. R., Klemm, L.R. (Louis Richard), 1845-1925., Klemm, L. R., and Klemm, L.R. (Louis Richard), 1845-1925.

Abstract

We have determined this item to be in the public domain according to US copyright law through information in the bibliographic record and/or US copyright renewal records. The digital version is available for all educational uses worldwide. Please contact HathiTrust staff at hathitrust-help@umich.edu with any questions about this item., German poetry., (LCCN)32019453., (OCoLC)16770039., Sdr-nrlfGLAD17146000-B., PT1155 .K55 1881., 831.08., Http://hdl.handle.net/2027/uc1.b257078.

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