Sunhee Serenity Kim

All Publications

• Parp3 promotes long-range end joining in murine cells PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Layer, J., Cleary, J., Brown, A. J., Stevenson, K. E., Morrow, S. N., Van Scoyk, A., Blasco, R. B., Karaca, E., Meng, F., Frock, R. L., Tivey, T., Kim, S., Fuchs, H., Chiarle, R., Alt, F. W., Roberts, S. A., Weinstock, D. M., Day, T. A. 2018; 115 (40): 10076–81

  Abstract

  Chromosomal rearrangements, including translocations, are early and essential events in the formation of many tumors. Previous studies that defined the genetic requirements for rearrangement formation have identified differences between murine and human cells, most notably in the role of classic and alternative nonhomologous end-joining (NHEJ) factors. We reported that poly(ADP)ribose polymerase 3 (PARP3) promotes chromosomal rearrangements induced by endonucleases in multiple human cell types. We show here that in contrast to classic (c-NHEJ) factors, Parp3 also promotes rearrangements in murine cells, including translocations in murine embryonic stem cells (mESCs), class-switch recombination in primary B cells, and inversions in tail fibroblasts that generate Eml4-Alk fusions. In mESCs, Parp3-deficient cells had shorter deletion lengths at translocation junctions. This was corroborated using next-generation sequencing of Eml4-Alk junctions in tail fibroblasts and is consistent with a role for Parp3 in promoting the processing of DNA double-strand breaks. We confirmed a previous report that Parp1 also promotes rearrangement formation. In contrast with Parp3, rearrangement junctions in the absence of Parp1 had longer deletion lengths, suggesting that Parp1 may suppress double-strand break processing. Together, these data indicate that Parp3 and Parp1 promote rearrangements with distinct phenotypes.

  View details for DOI 10.1073/pnas.1801591115

  View details for Web of Science ID 000446078700075

  View details for PubMedID 30213852

  View details for PubMedCentralID PMC6176633

• Pediatric-type nodal follicular lymphoma: a biologically distinct lymphoma with frequent MAPK pathway mutations. Blood Louissaint, A., Schafernak, K. T., Geyer, J. T., Kovach, A. E., Ghandi, M., Gratzinger, D., Roth, C. G., Paxton, C. N., Kim, S., Namgyal, C., Morin, R., Morgan, E. A., Neuberg, D. S., South, S. T., Harris, M. H., Hasserjian, R. P., Hochberg, E. P., Garraway, L. A., Harris, N. L., Weinstock, D. M. 2016; 128 (8): 1093-1100

  Abstract

  Pediatric-type nodal follicular lymphoma (PTNFL) is a variant of follicular lymphoma (FL) characterized by limited-stage presentation and invariably benign behavior despite often high-grade histological appearance. It is important to distinguish PTNFL from typical FL in order to avoid unnecessary treatment; however, this distinction relies solely on clinical and pathological criteria, which may be variably applied. To define the genetic landscape of PTNFL, we performed copy-number analysis, exome and/or targeted sequencing of 26 PTNFLs (16 pediatric, 10 adult). The most commonly mutated gene in PTNFL was MAP2K1, encoding MEK1, with a mutation frequency of 43%. All MAP2K1 mutations were activating missense mutations localized to exons 2 and 3, which encode negative regulatory and catalytic domains, respectively. Missense mutations in MAPK1 (2/22), and RRAS (1/22) were identified in cases that lacked MAP2K1 mutations. The second most commonly mutated gene in PTNFL was TNFRSF14, with a mutation frequency of 29%, similar to that seen in limited-stage typical FL (p=0.35). PTNFL was otherwise genomically bland, and specifically lacked recurrent mutations in epigenetic modifiers (e.g. CREBBP, KMT2D). Copy number aberrations (CNAs) affected a mean of only 0.5% of PTNFL genomes, compared to 10% of limited-stage typical FL genomes (p<0.02). Importantly, the mutational profiles of PTNFLs in children and adults were highly similar. Together, these findings define PTNFL as a biologically and clinically distinct indolent lymphoma of children and adults characterized by a high prevalence of MAP kinase pathway mutations and a near absence of mutations in epigenetic modifiers.

  View details for DOI 10.1182/blood-2015-12-682591

  View details for PubMedID 27325104

• Pediatric-Type Nodal Follicular Lymphoma in Children and Adults Is Nearly Genetically Silent and Biologically Distinct from Typical Follicular Lymphoma Louissaint, A., Schafernak, K. T., Geyer, J. T., Kovach, A. E., Gratzinger, D., Roth, C. G., Paxton, C. N., Kim, S., Namgyal, C., Morgan, E. A., South, S. T., Harris, M. H., Hochberg, E. P., Hasserjian, R. P., Harris, N. L., Weinstock, D. M. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368021800182

• Mutations in G protein beta subunits promote transformation and kinase inhibitor resistance NATURE MEDICINE Yoda, A., Adelmant, G., Tamburini, J., Chapuy, B., Shindoh, N., Yoda, Y., Weigert, O., Kopp, N., Wu, S., Kim, S. S., Liu, H., Tivey, T., Christie, A. L., Elpek, K. G., Card, J., Gritsman, K., Gotlib, J., Deininger, M. W., Makishima, H., Turley, S. J., Javidi-Sharifi, N., Maciejewski, J. P., Jaiswal, S., Ebert, B. L., Rodig, S. J., Tyner, J. W., Marto, J. A., Weinstock, D. M., Lane, A. A. 2015; 21 (1): 71-75

  Abstract

  Activating mutations in genes encoding G protein α (Gα) subunits occur in 4-5% of all human cancers, but oncogenic alterations in Gβ subunits have not been defined. Here we demonstrate that recurrent mutations in the Gβ proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Gα subunits as well as downstream effectors and disrupt Gα interactions with the Gβγ dimer. Different mutations in Gβ proteins clustered partly on the basis of lineage; for example, all 11 GNB1 K57 mutations were in myeloid neoplasms, and seven of eight GNB1 I80 mutations were in B cell neoplasms. Expression of patient-derived GNB1 variants in Cdkn2a-deficient mouse bone marrow followed by transplantation resulted in either myeloid or B cell malignancies. In vivo treatment with the dual PI3K-mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival. In several human tumors, mutations in the gene encoding GNB1 co-occurred with oncogenic kinase alterations, including the BCR-ABL fusion protein, the V617F substitution in JAK2 and the V600K substitution in BRAF. Coexpression of patient-derived GNB1 variants with these mutant kinases resulted in inhibitor resistance in each context. Thus, GNB1 and GNB2 alterations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling.

  View details for DOI 10.1038/nm.3751

  View details for PubMedID 25485910

• GNB1 Activating Mutations Promote Myeloid and Lymphoid Neoplasms Targetable By Combined PI3K/mTOR Inhibition Yoda, A., Adelmant, G., Tamburini, J., Chapuy, B., Shindoh, N., Yoda, Y., Weigert, O., Kopp, N., Wu, S., Kim, S. S., Liu, H., Tivey, T., Christie, A. L., Elpek, K. G., Card, J., Gritsman, K., Gotlib, J., Deininger, M. W., Makishima, H., Turley, S., Javidi-Sharifi, N., Maciejewski, J. P., Rodig, S. J., Tyner, J. W., Marto, J. A., Weinstock, D. M., Lane, A. A. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349242702149