Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia

• Published in: Nature communications Vol. 14; no. 1; pp. 809 - 13
• Main Authors: Kamens, Jennifer L., Nance, Stephanie, Koss, Cary, Xu, Beisi, Cotton, Anitria, Lam, Jeannie W., Garfinkle, Elizabeth A. R., Nallagatla, Pratima, Smith, Amelia M. R., Mitchell, Sharnise, Ma, Jing, Currier, Duane, Wright, William C., Kavdia, Kanisha, Pagala, Vishwajeeth R., Kim, Wonil, Wallace, LaShanale M., Cho, Ji-Hoon, Fan, Yiping, Seth, Aman, Twarog, Nathaniel, Choi, John K., Obeng, Esther A., Hatley, Mark E., Metzger, Monika L., Inaba, Hiroto, Jeha, Sima, Rubnitz, Jeffrey E., Peng, Junmin, Chen, Taosheng, Shelat, Anang A., Guy, R. Kiplin, Gruber, Tanja A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.02.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 45/15; 45/91; 49/47; 631/67/1990/283/2125; 631/67/2332; 64/60; 82/58; Acute lymphoblastic leukemia; Adult; Babies; Chemotherapy; Child; Depletion; Drug screening; Gene expression; Histone H2B; Histone H3; Histone methyltransferase; Histones; Humanities and Social Sciences; Humans; Infant; Infants; Leukemia; Lymphatic leukemia; Lysine; Lysine - genetics; Medical prognosis; Methylation; Methyltransferase; MLL protein; multidisciplinary; Myeloid-Lymphoid Leukemia Protein - genetics; N-Methyltransferase; Patients; Pediatrics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Prognosis; Proteasome Endopeptidase Complex - genetics; Proteasomes; Science; Science (multidisciplinary); Transcriptome; Ubiquitination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36370-x

Rearrangments in Histone-lysine-N-methyltransferase 2A (KMT2Ar) are associated with pediatric, adult and therapy-induced acute leukemias. Infants with KMT2Ar acute lymphoblastic leukemia (ALL) have a poor prognosis with an event-free-survival of 38%. Herein we evaluate 1116 FDA approved compounds in primary KMT2Ar infant ALL specimens and identify a sensitivity to proteasome inhibition. Upon exposure to this class of agents, cells demonstrate a depletion of histone H2B monoubiquitination (H2Bub1) and histone H3 lysine 79 dimethylation (H3K79me2) at KMT2A target genes in addition to a downregulation of the KMT2A gene expression signature, providing evidence that it targets the KMT2A transcriptional complex and alters the epigenome. A cohort of relapsed/refractory KMT2Ar patients treated with this approach on a compassionate basis had an overall response rate of 90%. In conclusion, we report on a high throughput drug screen in primary pediatric leukemia specimens whose results translate into clinically meaningful responses. This innovative treatment approach is now being evaluated in a multi-institutional upfront trial for infants with newly diagnosed ALL. KMT2A rearranged infant acute lymphoblastic leukemia patients have a poor prognosis. Here, the authors use high throughput drug screening on primary infant specimens to identify a clinically active chemotherapy combination.