Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia

Jennifer L Kamens; Stephanie Nance; Cary Koss; Beisi Xu; Anitria Cotton; Jeannie W Lam; Elizabeth A R Garfinkle; Pratima Nallagatla; Amelia M R Smith; Sharnise Mitchell; Jing Ma; Duane Currier; William C Wright; Kanisha Kavdia; Vishwajeeth R Pagala; Wonil Kim; LaShanale M Wallace; Ji-Hoon Cho; Yiping Fan; Aman Seth; Nathaniel Twarog; John K Choi; Esther A Obeng; Mark E Hatley; Monika L Metzger; Hiroto Inaba; Sima Jeha; Jeffrey E Rubnitz; Junmin Peng; Taosheng Chen; Anang A Shelat; R Kiplin Guy; Tanja A Gruber

doi:10.1038/s41467-023-36370-x

Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia

Jennifer L Kamens
, Stephanie Nance
, Cary Koss
, Beisi Xu
, Anitria Cotton
, Jeannie W Lam
, Elizabeth A R Garfinkle
, Pratima Nallagatla
, Amelia M R Smith
, Sharnise Mitchell
, Jing Ma
, Duane Currier
, William C Wright
, Kanisha Kavdia
, Vishwajeeth R Pagala
, Wonil Kim
, LaShanale M Wallace
, Ji-Hoon Cho
, Yiping Fan
, Aman Seth

Nathaniel Twarog, John K Choi, Esther A Obeng, Mark E Hatley, Monika L Metzger, Hiroto Inaba, Sima Jeha, Jeffrey E Rubnitz, Junmin Peng, Taosheng Chen, Anang A Shelat, R Kiplin Guy, Tanja A Gruber

Producción científica: Article › revisión exhaustiva

18 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	809
Publicación	Nature Communications
Volumen	14
N.º	1
DOI	https://doi.org/10.1038/s41467-023-36370-x
Estado	Published - feb 13 2023

Nota bibliográfica

Financiación

The authors thank all the members of the St Jude Children’s Research Hospital for their support. We specifically thank the staff of the Animal Resource Center, Tissue Resources Laboratory, Flow Cytometry and Cell Sorting Core, Cell and Tissue Imaging, Proteomics & Metabolomics, and the Hartwell Center for Biotechnology and Bioinformatics. This work was supported by grants from the V Foundation, and the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude Children’s Research Hospital. The authors thank all the members of the St Jude Children’s Research Hospital for their support. We specifically thank the staff of the Animal Resource Center, Tissue Resources Laboratory, Flow Cytometry and Cell Sorting Core, Cell and Tissue Imaging, Proteomics & Metabolomics, and the Hartwell Center for Biotechnology and Bioinformatics. This work was supported by grants from the V Foundation, and the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude Children’s Research Hospital.

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Kamens, J. L., Nance, S., Koss, C., Xu, B., Cotton, A., Lam, J. W., Garfinkle, E. A. R., Nallagatla, P., Smith, A. M. R., Mitchell, S., Ma, J., Currier, D., Wright, W. C., Kavdia, K., Pagala, V. R., Kim, W., Wallace, L. M., Cho, J.-H., Fan, Y., ... Gruber, T. A. (2023). Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia. Nature Communications, 14(1), 809. https://doi.org/10.1038/s41467-023-36370-x

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title = "Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia",

abstract = "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.",

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Kamens, JL, Nance, S, Koss, C, Xu, B, Cotton, A, Lam, JW, Garfinkle, EAR, Nallagatla, P, Smith, AMR, Mitchell, S, Ma, J, Currier, D, Wright, WC, Kavdia, K, Pagala, VR, Kim, W, Wallace, LM, Cho, J-H, Fan, Y, Seth, A, Twarog, N, Choi, JK, Obeng, EA, Hatley, ME, Metzger, ML, Inaba, H, Jeha, S, Rubnitz, JE, Peng, J, Chen, T, Shelat, AA, Guy, RK & Gruber, TA 2023, 'Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia', Nature Communications, vol. 14, n.º 1, pp. 809. https://doi.org/10.1038/s41467-023-36370-x

TY - JOUR

T1 - Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia

AU - Kamens, Jennifer L

AU - Nance, Stephanie

AU - Koss, Cary

AU - Xu, Beisi

AU - Cotton, Anitria

AU - Lam, Jeannie W

AU - Garfinkle, Elizabeth A R

AU - Nallagatla, Pratima

AU - Smith, Amelia M R

AU - Mitchell, Sharnise

AU - Ma, Jing

AU - Currier, Duane

AU - Wright, William C

AU - Kavdia, Kanisha

AU - Pagala, Vishwajeeth R

AU - Kim, Wonil

AU - Wallace, LaShanale M

AU - Cho, Ji-Hoon

AU - Fan, Yiping

AU - Seth, Aman

AU - Twarog, Nathaniel

AU - Choi, John K

AU - Obeng, Esther A

AU - Hatley, Mark E

AU - Metzger, Monika L

AU - Inaba, Hiroto

AU - Jeha, Sima

AU - Rubnitz, Jeffrey E

AU - Peng, Junmin

AU - Chen, Taosheng

AU - Shelat, Anang A

AU - Guy, R Kiplin

AU - Gruber, Tanja A

PY - 2023/2/13

Y1 - 2023/2/13

N2 - 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.

AB - 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.

KW - Infant

KW - Adult

KW - Humans

KW - Child

KW - Proteasome Endopeptidase Complex/genetics

KW - Lysine/genetics

KW - Myeloid-Lymphoid Leukemia Protein/genetics

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy

KW - Transcriptome

U2 - 10.1038/s41467-023-36370-x

DO - 10.1038/s41467-023-36370-x

M3 - Article

C2 - 36781850

SN - 2041-1723

VL - 14

SP - 809

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia

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