Acute Lymphoblastic Leukemia

Wynn, Robert

doi:10.1002/9781444315134.ch7

Cited by 1 publication

(1 citation statement)

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“…Enhanced proliferation and clonogenicity of mutant cells were likely not primary reasons for increased lethality, however. NSD2 WT/E1099K cells also exhibited earlier invasion of the central nervous system, a common site of relapse in pediatric ALL (48). Interestingly, the mutant cells also invade the brain parenchyma, a clinically rare but significant finding, which is likely the major reason for their increased lethality because general tumor burden was not predictive of death.…”

Section: Discussionmentioning

confidence: 99%

An activating mutation of the NSD2 histone methyltransferase drives oncogenic reprogramming in acute lymphocytic leukemia

et al. 2018

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NSD2, a histone methyltransferase specific for methylation of histone 3 lysine 36 (H3K36), exhibits a glutamic acid to lysine mutation at residue 1099 (E1099K) in childhood acute lymphocytic leukemia (ALL), and cells harboring this mutation can become the predominant clone in relapsing disease. We studied the effects of this mutant enzyme in silico, in vitro, and in vivo using gene edited cell lines. The E1099K mutation altered enzyme/substrate binding and enhanced the rate of H3K36 methylation. As a result, cell lines harboring E1099K exhibit increased H3K36 dimethylation and reduced H3K27 trimethylation, particularly on nucleosomes containing histone H3.1. Mutant NSD2 cells exhibit reduced apoptosis and enhanced proliferation, clonogenicity, adhesion, and migration. In mouse xenografts, mutant NSD2 cells are more lethal and brain invasive than wildtype cells. Transcriptional profiling demonstrates that mutant NSD2 aberrantly activates factors commonly associated with neural and stromal lineages in addition to signaling and adhesion genes. Identification of these pathways provides new avenues for therapeutic interventions in NSD2 dysregulated malignancies.

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Section: Discussionmentioning

confidence: 99%