In Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities

Elisa ten Hacken; Tomasz Sewastianik; Shanye Yin; Gabriela Brunsting Hoffmann; Michaela Gruber; Kendell Clement; Livius Penter; Robert A. Redd; Neil Ruthen; Sébastien Hergalant; Alanna Sholokhova; Geoffrey Fell; Erin M. Parry; Julien Broséus; Romain Guieze; Fabienne Lucas; María Hernández-Sánchez; Kaitlyn Baranowski; Jackson Southard; Heather Joyal; Leah Billington; Fara Faye D. Regis; Elizabeth Witten; Mohamed Uduman; Binyamin A. Knisbacher; Shuqiang Li; Haoxiang Lyu; Tiziana Vaisitti; Silvia Deaglio; Giorgio Inghirami; Pierre Feugier; Stephan Stilgenbauer; Eugen Tausch; Matthew S. Davids; Gad Getz; Kenneth J. Livak; Ivana Bozic; Donna S. Neuberg; Ruben D. Carrasco; Catherine J. Wu

doi:10.1158/2643-3230.BCD-22-0082

In Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities

Elisa ten Hacken, Tomasz Sewastianik, Shanye Yin, Gabriela Brunsting Hoffmann, Michaela Gruber, Kendell Clement, Livius Penter, Robert A. Redd, Neil Ruthen, Sébastien Hergalant, Alanna Sholokhova, Geoffrey Fell, Erin M. Parry, Julien Broséus, Romain Guieze, Fabienne Lucas, María Hernández-Sánchez, Kaitlyn Baranowski, Jackson Southard, Heather JoyalLeah Billington, Fara Faye D. Regis, Elizabeth Witten, Mohamed Uduman, Binyamin A. Knisbacher, Shuqiang Li, Haoxiang Lyu, Tiziana Vaisitti, Silvia Deaglio, Giorgio Inghirami, Pierre Feugier, Stephan Stilgenbauer, Eugen Tausch, Matthew S. Davids, Gad Getz, Kenneth J. Livak, Ivana Bozic, Donna S. Neuberg, Ruben D. Carrasco, Catherine J. Wu

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

13 Scopus citations

Abstract

Transformation to aggressive disease histologies generates formidable clinical challenges across cancers, but biological insights remain few. We modeled the genetic heterogeneity of chronic lymphocytic leukemia (CLL) through multiplexed in vivo CRISPR-Cas9 B-cell editing of recurrent CLL loss-of-function drivers in mice and recapitulated the process of transformation from indolent CLL into large cell lymphoma [i.e., Richter syndrome (RS)]. Evolutionary trajectories of 64 mice carrying diverse combinatorial gene assortments revealed coselection of mutations in Trp53, Mga, and Chd2 and the dual impact of clonal Mga/Chd2 mutations on E2F/MYC and interferon signaling dysregulation. Comparative human and murine RS analyses demonstrated tonic PI3K signaling as a key feature of transformed disease, with constitutive activation of the AKT and S6 kinases, downmodulation of the PTEN phosphatase, and convergent activation of MYC/PI3K transcriptional programs underlying enhanced sensitivity to MYC/mTOR/PI3K inhibition. This robust experimental system presents a unique framework to study lymphoid biology and therapy.

Original language	English
Pages (from-to)	150-169
Number of pages	20
Journal	Blood cancer discovery
Volume	4
Issue number	2
DOIs	https://doi.org/10.1158/2643-3230.BCD-22-0082
State	Published - 1 Mar 2023
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2022 American Association for Cancer Research.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1158/2643-3230.BCD-22-0082

Cite this

ten Hacken, E., Sewastianik, T., Yin, S., Hoffmann, G. B., Gruber, M., Clement, K., Penter, L., Redd, R. A., Ruthen, N., Hergalant, S., Sholokhova, A., Fell, G., Parry, E. M., Broséus, J., Guieze, R., Lucas, F., Hernández-Sánchez, M., Baranowski, K., Southard, J., ... Wu, C. J. (2023). In Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities. Blood cancer discovery, 4(2), 150-169. https://doi.org/10.1158/2643-3230.BCD-22-0082

@article{73bcdcf91dc84bc8b909e88912c5d6e0,

title = "In Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities",

abstract = "Transformation to aggressive disease histologies generates formidable clinical challenges across cancers, but biological insights remain few. We modeled the genetic heterogeneity of chronic lymphocytic leukemia (CLL) through multiplexed in vivo CRISPR-Cas9 B-cell editing of recurrent CLL loss-of-function drivers in mice and recapitulated the process of transformation from indolent CLL into large cell lymphoma [i.e., Richter syndrome (RS)]. Evolutionary trajectories of 64 mice carrying diverse combinatorial gene assortments revealed coselection of mutations in Trp53, Mga, and Chd2 and the dual impact of clonal Mga/Chd2 mutations on E2F/MYC and interferon signaling dysregulation. Comparative human and murine RS analyses demonstrated tonic PI3K signaling as a key feature of transformed disease, with constitutive activation of the AKT and S6 kinases, downmodulation of the PTEN phosphatase, and convergent activation of MYC/PI3K transcriptional programs underlying enhanced sensitivity to MYC/mTOR/PI3K inhibition. This robust experimental system presents a unique framework to study lymphoid biology and therapy.",

author = "{ten Hacken}, Elisa and Tomasz Sewastianik and Shanye Yin and Hoffmann, {Gabriela Brunsting} and Michaela Gruber and Kendell Clement and Livius Penter and Redd, {Robert A.} and Neil Ruthen and S{\'e}bastien Hergalant and Alanna Sholokhova and Geoffrey Fell and Parry, {Erin M.} and Julien Bros{\'e}us and Romain Guieze and Fabienne Lucas and Mar{\'i}a Hern{\'a}ndez-S{\'a}nchez and Kaitlyn Baranowski and Jackson Southard and Heather Joyal and Leah Billington and Regis, {Fara Faye D.} and Elizabeth Witten and Mohamed Uduman and Knisbacher, {Binyamin A.} and Shuqiang Li and Haoxiang Lyu and Tiziana Vaisitti and Silvia Deaglio and Giorgio Inghirami and Pierre Feugier and Stephan Stilgenbauer and Eugen Tausch and Davids, {Matthew S.} and Gad Getz and Livak, {Kenneth J.} and Ivana Bozic and Neuberg, {Donna S.} and Carrasco, {Ruben D.} and Wu, {Catherine J.}",

note = "Publisher Copyright: {\textcopyright} 2022 American Association for Cancer Research.",

year = "2023",

month = mar,

day = "1",

doi = "10.1158/2643-3230.BCD-22-0082",

language = "אנגלית",

volume = "4",

pages = "150--169",

journal = "Blood cancer discovery",

issn = "2643-3230",

publisher = "NLM (Medline)",

number = "2",

}

ten Hacken, E, Sewastianik, T, Yin, S, Hoffmann, GB, Gruber, M, Clement, K, Penter, L, Redd, RA, Ruthen, N, Hergalant, S, Sholokhova, A, Fell, G, Parry, EM, Broséus, J, Guieze, R, Lucas, F, Hernández-Sánchez, M, Baranowski, K, Southard, J, Joyal, H, Billington, L, Regis, FFD, Witten, E, Uduman, M, Knisbacher, BA, Li, S, Lyu, H, Vaisitti, T, Deaglio, S, Inghirami, G, Feugier, P, Stilgenbauer, S, Tausch, E, Davids, MS, Getz, G, Livak, KJ, Bozic, I, Neuberg, DS, Carrasco, RD & Wu, CJ 2023, 'In Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities', Blood cancer discovery, vol. 4, no. 2, pp. 150-169. https://doi.org/10.1158/2643-3230.BCD-22-0082

TY - JOUR

T1 - In Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities

AU - ten Hacken, Elisa

AU - Sewastianik, Tomasz

AU - Yin, Shanye

AU - Hoffmann, Gabriela Brunsting

AU - Gruber, Michaela

AU - Clement, Kendell

AU - Penter, Livius

AU - Redd, Robert A.

AU - Ruthen, Neil

AU - Hergalant, Sébastien

AU - Sholokhova, Alanna

AU - Fell, Geoffrey

AU - Parry, Erin M.

AU - Broséus, Julien

AU - Guieze, Romain

AU - Lucas, Fabienne

AU - Hernández-Sánchez, María

AU - Baranowski, Kaitlyn

AU - Southard, Jackson

AU - Joyal, Heather

AU - Billington, Leah

AU - Regis, Fara Faye D.

AU - Witten, Elizabeth

AU - Uduman, Mohamed

AU - Knisbacher, Binyamin A.

AU - Li, Shuqiang

AU - Lyu, Haoxiang

AU - Vaisitti, Tiziana

AU - Deaglio, Silvia

AU - Inghirami, Giorgio

AU - Feugier, Pierre

AU - Stilgenbauer, Stephan

AU - Tausch, Eugen

AU - Davids, Matthew S.

AU - Getz, Gad

AU - Livak, Kenneth J.

AU - Bozic, Ivana

AU - Neuberg, Donna S.

AU - Carrasco, Ruben D.

AU - Wu, Catherine J.

PY - 2023/3/1

Y1 - 2023/3/1

N2 - Transformation to aggressive disease histologies generates formidable clinical challenges across cancers, but biological insights remain few. We modeled the genetic heterogeneity of chronic lymphocytic leukemia (CLL) through multiplexed in vivo CRISPR-Cas9 B-cell editing of recurrent CLL loss-of-function drivers in mice and recapitulated the process of transformation from indolent CLL into large cell lymphoma [i.e., Richter syndrome (RS)]. Evolutionary trajectories of 64 mice carrying diverse combinatorial gene assortments revealed coselection of mutations in Trp53, Mga, and Chd2 and the dual impact of clonal Mga/Chd2 mutations on E2F/MYC and interferon signaling dysregulation. Comparative human and murine RS analyses demonstrated tonic PI3K signaling as a key feature of transformed disease, with constitutive activation of the AKT and S6 kinases, downmodulation of the PTEN phosphatase, and convergent activation of MYC/PI3K transcriptional programs underlying enhanced sensitivity to MYC/mTOR/PI3K inhibition. This robust experimental system presents a unique framework to study lymphoid biology and therapy.

AB - Transformation to aggressive disease histologies generates formidable clinical challenges across cancers, but biological insights remain few. We modeled the genetic heterogeneity of chronic lymphocytic leukemia (CLL) through multiplexed in vivo CRISPR-Cas9 B-cell editing of recurrent CLL loss-of-function drivers in mice and recapitulated the process of transformation from indolent CLL into large cell lymphoma [i.e., Richter syndrome (RS)]. Evolutionary trajectories of 64 mice carrying diverse combinatorial gene assortments revealed coselection of mutations in Trp53, Mga, and Chd2 and the dual impact of clonal Mga/Chd2 mutations on E2F/MYC and interferon signaling dysregulation. Comparative human and murine RS analyses demonstrated tonic PI3K signaling as a key feature of transformed disease, with constitutive activation of the AKT and S6 kinases, downmodulation of the PTEN phosphatase, and convergent activation of MYC/PI3K transcriptional programs underlying enhanced sensitivity to MYC/mTOR/PI3K inhibition. This robust experimental system presents a unique framework to study lymphoid biology and therapy.

UR - http://www.scopus.com/inward/record.url?scp=85149152983&partnerID=8YFLogxK

U2 - 10.1158/2643-3230.BCD-22-0082

DO - 10.1158/2643-3230.BCD-22-0082

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 36468984

AN - SCOPUS:85149152983

SN - 2643-3230

VL - 4

SP - 150

EP - 169

JO - Blood cancer discovery

JF - Blood cancer discovery

IS - 2

ER -

In Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities

Abstract

Bibliographical note

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this