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2 results on '"Chan, Lai N."'

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

Author

Shojaee, Seyedmehdi, Caeser, Rebecca, Buchner, Maike, Park, Eugene, Swaminathan, Srividya, Hurtz, Christian, Geng, Huimin, Chan, Lai N, Klemm, Lars, Hofmann, Wolf-Karsten, Qiu, Yi Hua, Zhang, Nianxiang, Coombes, Kevin R, Paietta, Elisabeth, Molkentin, Jeffery, Koeffler, H Phillip, Willman, Cheryl L, Hunger, Stephen P, Melnick, Ari, Kornblau, Steven M, and Müschen, Markus

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Cancer, Pediatric, Childhood Leukemia, Pediatric Cancer, Rare Diseases, Hematology, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Aetiology, Animals, Antineoplastic Agents, Cell Transformation, Neoplastic, DNA-Binding Proteins, Dual Specificity Phosphatase 6, Host Cell Factor C1, Humans, Intracellular Signaling Peptides and Proteins, MAP Kinase Signaling System, Membrane Proteins, Mice, Mice, Transgenic, Molecular Sequence Data, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, Protein Serine-Threonine Kinases, Small Molecule Libraries, Transcription Factors, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Studying mechanisms of malignant transformation of human pre-B cells, we found that acute activation of oncogenes 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 of Erk 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 models for 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.

Published
2015

2. Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia

Author

Geng, Huimin, Hurtz, Christian, Lenz, Kyle B, Chen, Zhengshan, Baumjohann, Dirk, Thompson, Sarah, Goloviznina, Natalya A, Chen, Wei-Yi, Huan, Jianya, LaTocha, Dorian, Ballabio, Erica, Xiao, Gang, Lee, Jae-Woong, Deucher, Anne, Qi, Zhongxia, Park, Eugene, Huang, Chuanxin, Nahar, Rahul, Kweon, Soo-Mi, Shojaee, Seyedmehdi, Chan, Lai N, Yu, Jingwei, Kornblau, Steven M, Bijl, Janetta J, Ye, B Hilda, Ansel, K Mark, Paietta, Elisabeth, Melnick, Ari, Hunger, Stephen P, Kurre, Peter, Tyner, Jeffrey W, Loh, Mignon L, Roeder, Robert G, Druker, Brian J, Burger, Jan A, Milne, Thomas A, Chang, Bill H, and Müschen, Markus

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Pediatric, Childhood Leukemia, Vaccine Related, Cancer, Hematology, Pediatric Cancer, Basic Helix-Loop-Helix Transcription Factors, Clinical Trials as Topic, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins, Molecular Sequence Data, Phosphatidylinositol 3-Kinase, Pre-B-Cell Leukemia Transcription Factor 1, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Precursor Cells, B-Lymphoid, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-6, Signal Transduction, Syk Kinase, Up-Regulation, src-Family Kinases, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Studying 830 pre-B ALL cases from four clinical trials, we found that human ALL can be divided into two fundamentally distinct subtypes based on pre-BCR function. While absent in the majority of ALL cases, tonic pre-BCR signaling was found in 112 cases (13.5%). In these cases, tonic pre-BCR signaling induced activation of BCL6, which in turn increased pre-BCR signaling output at the transcriptional level. Interestingly, inhibition of pre-BCR-related tyrosine kinases reduced constitutive BCL6 expression and selectively killed patient-derived pre-BCR(+) ALL cells. These findings identify a genetically and phenotypically distinct subset of human ALL that critically depends on tonic pre-BCR signaling. In vivo treatment studies suggested that pre-BCR tyrosine kinase inhibitors are useful for the treatment of patients with pre-BCR(+) ALL.

Published
2015

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