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

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

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.

Original language	English
Pages (from-to)	809
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-36370-x
State	Published - Feb 13 2023

Bibliographical note

Funding

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.

Keywords

Infant
Adult
Humans
Child
Proteasome Endopeptidase Complex/genetics
Lysine/genetics
Myeloid-Lymphoid Leukemia Protein/genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
Transcriptome

Access to Document

10.1038/s41467-023-36370-x

Cite this

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.",

keywords = "Infant, Adult, Humans, Child, Proteasome Endopeptidase Complex/genetics, Lysine/genetics, Myeloid-Lymphoid Leukemia Protein/genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy, Transcriptome",

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

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year = "2023",

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day = "13",

doi = "10.1038/s41467-023-36370-x",

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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, no. 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

Abstract

Bibliographical note

Funding

Keywords

Access to Document

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Cite this