Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement

Zach H. Gray; Damayanti Chakraborty; Reuben R. Duttweiler; Gulnaz D. Alekbaeva; Sedona E. Murphy; Kashish Chetal; Fei Ji; Benjamin I. Ferman; Madison A. Honer; Zhentian Wang; Cynthia Myers; Renhong Sun; H. Ümit Kaniskan; Monika Maria Toma; Elena A. Bondarenko; John N. Santoro; Christopher Miranda; Megan E. Dillingham; Ran Tang; Or Gozani; Jian Jin; Tomasz Skorski; Cihangir Duy; Hayan Lee; Ruslan I. Sadreyev; Johnathan R. Whetstine

doi:10.1016/j.cell.2023.09.009

Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement

Zach H. Gray, Damayanti Chakraborty, Reuben R. Duttweiler, Gulnaz D. Alekbaeva, Sedona E. Murphy, Kashish Chetal, Fei Ji, Benjamin I. Ferman, Madison A. Honer, Zhentian Wang, Cynthia Myers, Renhong Sun, H. Ümit Kaniskan, Monika Maria Toma, Elena A. Bondarenko, John N. Santoro, Christopher Miranda, Megan E. Dillingham, Ran Tang, Or GozaniJian Jin, Tomasz Skorski, Cihangir Duy, Hayan Lee, Ruslan I. Sadreyev, Johnathan R. Whetstine

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

8 Scopus citations

Abstract

MLL/KMT2A amplifications and translocations are prevalent in infant, adult, and therapy-induced leukemia. However, the molecular contributor(s) to these alterations are unclear. Here, we demonstrate that histone H3 lysine 9 mono- and di-methylation (H3K9me1/2) balance at the MLL/KMT2A locus regulates these amplifications and rearrangements. This balance is controlled by the crosstalk between lysine demethylase KDM3B and methyltransferase G9a/EHMT2. KDM3B depletion increases H3K9me1/2 levels and reduces CTCF occupancy at the MLL/KMT2A locus, in turn promoting amplification and rearrangements. Depleting CTCF is also sufficient to generate these focal alterations. Furthermore, the chemotherapy doxorubicin (Dox), which associates with therapy-induced leukemia and promotes MLL/KMT2A amplifications and rearrangements, suppresses KDM3B and CTCF protein levels. KDM3B and CTCF overexpression rescues Dox-induced MLL/KMT2A alterations. G9a inhibition in human cells or mice also suppresses MLL/KMT2A events accompanying Dox treatment. Therefore, MLL/KMT2A amplifications and rearrangements are controlled by epigenetic regulators that are tractable drug targets, which has clinical implications.

Original language	English
Pages (from-to)	4528-4545.e18
Journal	Cell
Volume	186
Issue number	21
DOIs	https://doi.org/10.1016/j.cell.2023.09.009
State	Published - Oct 12 2023

Keywords

Adult
Animals
Doxorubicin/pharmacology
Epigenesis, Genetic
Gene Rearrangement
Histocompatibility Antigens
Histone-Lysine N-Methyltransferase/genetics
Humans
Infant
Jumonji Domain-Containing Histone Demethylases/genetics
Leukemia/metabolism
Lysine/metabolism
Mice
Myeloid-Lymphoid Leukemia Protein/genetics
Translocation, Genetic
KDM3B
KMT2A
DNA amplification
CTCF
MLL
G9a
doxorubicin
H3K9me
ecDNA
rearrangements

Access to Document

10.1016/j.cell.2023.09.009

Cite this

Gray, Z. H., Chakraborty, D., Duttweiler, R. R., Alekbaeva, G. D., Murphy, S. E., Chetal, K., Ji, F., Ferman, B. I., Honer, M. A., Wang, Z., Myers, C., Sun, R., Kaniskan, H. Ü., Toma, M. M., Bondarenko, E. A., Santoro, J. N., Miranda, C., Dillingham, M. E., Tang, R., ... Whetstine, J. R. (2023). Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement. Cell, 186(21), 4528-4545.e18. https://doi.org/10.1016/j.cell.2023.09.009

@article{08beeb815b4a4ab489e2d8bdaf7d995a,

title = "Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement",

abstract = "MLL/KMT2A amplifications and translocations are prevalent in infant, adult, and therapy-induced leukemia. However, the molecular contributor(s) to these alterations are unclear. Here, we demonstrate that histone H3 lysine 9 mono- and di-methylation (H3K9me1/2) balance at the MLL/KMT2A locus regulates these amplifications and rearrangements. This balance is controlled by the crosstalk between lysine demethylase KDM3B and methyltransferase G9a/EHMT2. KDM3B depletion increases H3K9me1/2 levels and reduces CTCF occupancy at the MLL/KMT2A locus, in turn promoting amplification and rearrangements. Depleting CTCF is also sufficient to generate these focal alterations. Furthermore, the chemotherapy doxorubicin (Dox), which associates with therapy-induced leukemia and promotes MLL/KMT2A amplifications and rearrangements, suppresses KDM3B and CTCF protein levels. KDM3B and CTCF overexpression rescues Dox-induced MLL/KMT2A alterations. G9a inhibition in human cells or mice also suppresses MLL/KMT2A events accompanying Dox treatment. Therefore, MLL/KMT2A amplifications and rearrangements are controlled by epigenetic regulators that are tractable drug targets, which has clinical implications.",

keywords = "Adult, Animals, Doxorubicin/pharmacology, Epigenesis, Genetic, Gene Rearrangement, Histocompatibility Antigens, Histone-Lysine N-Methyltransferase/genetics, Humans, Infant, Jumonji Domain-Containing Histone Demethylases/genetics, Leukemia/metabolism, Lysine/metabolism, Mice, Myeloid-Lymphoid Leukemia Protein/genetics, Translocation, Genetic, KDM3B, KMT2A, DNA amplification, CTCF, MLL, G9a, doxorubicin, H3K9me, ecDNA, rearrangements",

author = "Gray, {Zach H.} and Damayanti Chakraborty and Duttweiler, {Reuben R.} and Alekbaeva, {Gulnaz D.} and Murphy, {Sedona E.} and Kashish Chetal and Fei Ji and Ferman, {Benjamin I.} and Honer, {Madison A.} and Zhentian Wang and Cynthia Myers and Renhong Sun and Kaniskan, {H. {\"U}mit} and Toma, {Monika Maria} and Bondarenko, {Elena A.} and Santoro, {John N.} and Christopher Miranda and Dillingham, {Megan E.} and Ran Tang and Or Gozani and Jian Jin and Tomasz Skorski and Cihangir Duy and Hayan Lee and Sadreyev, {Ruslan I.} and Whetstine, {Johnathan R.}",

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = oct,

day = "12",

doi = "10.1016/j.cell.2023.09.009",

language = "English",

volume = "186",

pages = "4528--4545.e18",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "21",

}

Gray, ZH, Chakraborty, D, Duttweiler, RR, Alekbaeva, GD, Murphy, SE, Chetal, K, Ji, F, Ferman, BI, Honer, MA, Wang, Z, Myers, C, Sun, R, Kaniskan, HÜ, Toma, MM, Bondarenko, EA, Santoro, JN, Miranda, C, Dillingham, ME, Tang, R, Gozani, O, Jin, J, Skorski, T , Duy, C , Lee, H, Sadreyev, RI & Whetstine, JR 2023, 'Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement', Cell, vol. 186, no. 21, pp. 4528-4545.e18. https://doi.org/10.1016/j.cell.2023.09.009

TY - JOUR

T1 - Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement

AU - Gray, Zach H.

AU - Chakraborty, Damayanti

AU - Duttweiler, Reuben R.

AU - Alekbaeva, Gulnaz D.

AU - Murphy, Sedona E.

AU - Chetal, Kashish

AU - Ji, Fei

AU - Ferman, Benjamin I.

AU - Honer, Madison A.

AU - Wang, Zhentian

AU - Myers, Cynthia

AU - Sun, Renhong

AU - Kaniskan, H. Ümit

AU - Toma, Monika Maria

AU - Bondarenko, Elena A.

AU - Santoro, John N.

AU - Miranda, Christopher

AU - Dillingham, Megan E.

AU - Tang, Ran

AU - Gozani, Or

AU - Jin, Jian

AU - Skorski, Tomasz

AU - Duy, Cihangir

AU - Lee, Hayan

AU - Sadreyev, Ruslan I.

AU - Whetstine, Johnathan R.

PY - 2023/10/12

Y1 - 2023/10/12

N2 - MLL/KMT2A amplifications and translocations are prevalent in infant, adult, and therapy-induced leukemia. However, the molecular contributor(s) to these alterations are unclear. Here, we demonstrate that histone H3 lysine 9 mono- and di-methylation (H3K9me1/2) balance at the MLL/KMT2A locus regulates these amplifications and rearrangements. This balance is controlled by the crosstalk between lysine demethylase KDM3B and methyltransferase G9a/EHMT2. KDM3B depletion increases H3K9me1/2 levels and reduces CTCF occupancy at the MLL/KMT2A locus, in turn promoting amplification and rearrangements. Depleting CTCF is also sufficient to generate these focal alterations. Furthermore, the chemotherapy doxorubicin (Dox), which associates with therapy-induced leukemia and promotes MLL/KMT2A amplifications and rearrangements, suppresses KDM3B and CTCF protein levels. KDM3B and CTCF overexpression rescues Dox-induced MLL/KMT2A alterations. G9a inhibition in human cells or mice also suppresses MLL/KMT2A events accompanying Dox treatment. Therefore, MLL/KMT2A amplifications and rearrangements are controlled by epigenetic regulators that are tractable drug targets, which has clinical implications.

AB - MLL/KMT2A amplifications and translocations are prevalent in infant, adult, and therapy-induced leukemia. However, the molecular contributor(s) to these alterations are unclear. Here, we demonstrate that histone H3 lysine 9 mono- and di-methylation (H3K9me1/2) balance at the MLL/KMT2A locus regulates these amplifications and rearrangements. This balance is controlled by the crosstalk between lysine demethylase KDM3B and methyltransferase G9a/EHMT2. KDM3B depletion increases H3K9me1/2 levels and reduces CTCF occupancy at the MLL/KMT2A locus, in turn promoting amplification and rearrangements. Depleting CTCF is also sufficient to generate these focal alterations. Furthermore, the chemotherapy doxorubicin (Dox), which associates with therapy-induced leukemia and promotes MLL/KMT2A amplifications and rearrangements, suppresses KDM3B and CTCF protein levels. KDM3B and CTCF overexpression rescues Dox-induced MLL/KMT2A alterations. G9a inhibition in human cells or mice also suppresses MLL/KMT2A events accompanying Dox treatment. Therefore, MLL/KMT2A amplifications and rearrangements are controlled by epigenetic regulators that are tractable drug targets, which has clinical implications.

KW - Adult

KW - Animals

KW - Doxorubicin/pharmacology

KW - Epigenesis, Genetic

KW - Gene Rearrangement

KW - Histocompatibility Antigens

KW - Histone-Lysine N-Methyltransferase/genetics

KW - Humans

KW - Infant

KW - Jumonji Domain-Containing Histone Demethylases/genetics

KW - Leukemia/metabolism

KW - Lysine/metabolism

KW - Mice

KW - Myeloid-Lymphoid Leukemia Protein/genetics

KW - Translocation, Genetic

KW - KDM3B

KW - KMT2A

KW - DNA amplification

KW - CTCF

KW - MLL

KW - G9a

KW - doxorubicin

KW - H3K9me

KW - ecDNA

KW - rearrangements

UR - http://dx.doi.org/10.1016/j.cell.2023.09.009

U2 - 10.1016/j.cell.2023.09.009

DO - 10.1016/j.cell.2023.09.009

M3 - Article

C2 - 37788669

SN - 0092-8674

VL - 186

SP - 4528-4545.e18

JO - Cell

JF - Cell

IS - 21

ER -

Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Fox Chase Cancer Center Details Findings in Life Sciences (Epigenetic Balance Ensures Mechanistic Control Of Mll Amplification and Rearrangement)

Cell Culture Facility

Cell Sorting Facility

Cite this

Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Press/Media

Fox Chase Cancer Center Details Findings in Life Sciences (Epigenetic Balance Ensures Mechanistic Control Of Mll Amplification and Rearrangement)

Equipment

Cell Culture Facility

Cell Sorting Facility

Cite this