Pax5 loss imposes a reversible differentiation block in B-progenitor acute lymphoblastic leukemia

被引:67
|
作者
Liu, Grace J. [1 ,2 ]
Cimmino, Luisa [1 ,2 ]
Jude, Julian G. [3 ]
Hu, Yifang [4 ]
Witkowski, Matthew T. [1 ,2 ]
McKenzie, Mark D. [1 ,2 ]
Kartal-Kaess, Mutlu [1 ,2 ]
Best, Sarah A. [1 ,2 ]
Tuohey, Laura [1 ,2 ]
Liao, Yang [4 ,5 ]
Shi, Wei [4 ,5 ]
Mullighan, Charles G. [6 ]
Farrar, Michael A. [7 ]
Nutt, Stephen L. [8 ]
Smyth, Gordon K. [4 ,9 ]
Zuber, Johannes [3 ]
Dickins, Ross A. [1 ,2 ]
机构
[1] Walter & Eliza Hall Inst Med Res, Div Mol Med, Parkville, Vic 3052, Australia
[2] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010, Australia
[3] Vienna Bioctr, Res Inst Mol Pathol, A-1030 Vienna, Austria
[4] Walter & Eliza Hall Inst Med Res, Bioinformat Div, Parkville, Vic 3052, Australia
[5] Univ Melbourne, Dept Comp & Informat Syst, Parkville, Vic 3010, Australia
[6] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA
[7] Univ Minnesota, Mason Canc Ctr, Ctr Immunol, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA
[8] Walter & Eliza Hall Inst Med Res, Mol Immunol Div, Parkville, Vic 3052, Australia
[9] Univ Melbourne, Dept Math & Stat, Parkville, Vic 3010, Australia
基金
澳大利亚国家健康与医学研究理事会; 英国医学研究理事会; 澳大利亚研究理事会; 奥地利科学基金会; 美国国家卫生研究院;
关键词
PAX5; leukemia; B-ALL; differentiation; transcription factor; TRANSCRIPTION FACTOR PAX5; CELL RECEPTOR; BONE-MARROW; T-CELL; LYMPHOCYTE DIFFERENTIATION; CHAIN REARRANGEMENT; GENETIC ALTERATIONS; STAT5; ACTIVATION; PRO-B; C-MYC;
D O I
10.1101/gad.240416.114
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Loss-of-function mutations in hematopoietic transcription factors including PAX5 occur in most cases of B-progenitor acute lymphoblastic leukemia (B-ALL), a disease characterized by the accumulation of undifferentiated lymphoblasts. Although PAX5 mutation is a critical driver of B-ALL development in mice and humans, it remains unclear how its loss contributes to leukemogenesis and whether ongoing PAX5 deficiency is required for B-ALL maintenance. Here we used transgenic RNAi to reversibly suppress endogenous Pax5 expression in the hematopoietic compartment of mice, which cooperates with activated signal transducer and activator of transcription 5 (STAT5) to induce B-ALL. In this model, restoring endogenous Pax5 expression in established B-ALL triggers immunophenotypic maturation and durable disease remission by engaging a transcriptional program reminiscent of normal B-cell differentiation. Notably, even brief Pax5 restoration in B-ALL cells causes rapid cell cycle exit and disables their leukemia-initiating capacity. These and similar findings in human B-ALL cell lines establish that Pax5 hypomorphism promotes B-ALL self-renewal by impairing a differentiation program that can be re-engaged despite the presence of additional oncogenic lesions. Our results establish a causal relationship between the hallmark genetic and phenotypic features of B-ALL and suggest that engaging the latent differentiation potential of B-ALL cells may provide new therapeutic entry points.
引用
收藏
页码:1337 / 1350
页数:14
相关论文
共 50 条
  • [1] PAX5 LOSS IMPOSES A REVERSIBLE DIFFERENTIATION BLOCK IN B-PROGENITOR ACUTE LYMPHOBLASTIC LEUKEMIA
    Liu, Grace
    Cimmino, Luisa
    Jude, Julian
    Hu, Yifang
    Kartal, Mutlu
    Witkowski, Matthew
    McKenzie, Mark
    Best, Sarah
    Tuohey, Laura
    Mullighan, Charles
    Farrar, Michael
    Nutt, Stephen
    Smyth, Gordon
    Zuber, Johannes
    Dickins, Ross
    EXPERIMENTAL HEMATOLOGY, 2014, 42 (08) : S46 - S46
  • [2] PAX5 LOSS IMPOSES A REVERSIBLE DIFFERENTIATION BLOCK IN B-PROGENITOR ACUTE LYMPHOBLASTIC LEUKEMIA
    Dickins, Ross
    Liu, Grace
    Cimmino, Luisa
    Hu, Yifang
    Best, Sarah
    Tuohey, Laura
    Farrar, Michael
    Nutt, Stephen
    Smyth, Gordon
    EXPERIMENTAL HEMATOLOGY, 2013, 41 (08) : S16 - S16
  • [3] Retroviral and Chemical Mutagenesis Identifies Pax5 as a Tumor Suppressor in B-Progenitor Acute Lymphoblastic Leukemia
    Dang, Jinjun
    Mullighan, Charles G.
    Phillips, Letha A.
    Mehta, Perdeep
    Downing, James R.
    BLOOD, 2008, 112 (11) : 256 - 257
  • [4] Mutations in the B-Cell transcription factor PAX5 found in B-Progenitor acute lymphoblastic leukemia impair normal PAX5 activity.
    Miller, Christopher B.
    Mullighan, Charles G.
    Downing, James R.
    BLOOD, 2006, 108 (11) : 185A - 185A
  • [5] PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia
    Gu, Zhaohui
    Churchman, Michelle L.
    Roberts, Kathryn G.
    Moore, Ian
    Zhou, Xin
    Nakitandwe, Joy
    Hagiwara, Kohei
    Pelletier, Stephane
    Gingras, Sebastien
    Berns, Hartmut
    Payne-Turner, Debbie
    Hill, Ashley
    Iacobucci, Ilaria
    Shi, Lei
    Pounds, Stanley
    Cheng, Cheng
    Pei, Deqing
    Qu, Chunxu
    Newman, Scott
    Devidas, Meenakshi
    Dai, Yunfeng
    Reshmi, Shalini C.
    Gastier-Foster, Julie
    Raetz, Elizabeth A.
    Borowitz, Michael J.
    Wood, Brent L.
    Carroll, William L.
    Zweidler-McKay, Patrick A.
    Rabin, Karen R.
    Mattano, Leonard A.
    Maloney, Kelly W.
    Rambaldi, Alessandro
    Spinelli, Orietta
    Radich, Jerald P.
    Minden, Mark D.
    Rowe, Jacob M.
    Luger, Selina
    Litzow, Mark R.
    Tallman, Martin S.
    Racevskis, Janis
    Zhang, Yanming
    Bhatia, Ravi
    Kohlschmidt, Jessica
    Mrozek, Krzysztof
    Bloomfield, Clara D.
    Stock, Wendy
    Kornblau, Steven
    Kantarjian, Hagop M.
    Konopleva, Marina
    Evans, Williams E.
    NATURE GENETICS, 2019, 51 (02) : 296 - +
  • [6] Characterization of PAX5 Mutations in B Progenitor Acute Lymphoblastic Leukemia
    Jia, Zhilian
    Hu, Zunsong
    Damirchi, Behzad
    Han, Than Than
    Gu, Zhaohui
    BLOOD, 2022, 140 : 1001 - 1002
  • [7] PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia
    Zhaohui Gu
    Michelle L. Churchman
    Kathryn G. Roberts
    Ian Moore
    Xin Zhou
    Joy Nakitandwe
    Kohei Hagiwara
    Stephane Pelletier
    Sebastien Gingras
    Hartmut Berns
    Debbie Payne-Turner
    Ashley Hill
    Ilaria Iacobucci
    Lei Shi
    Stanley Pounds
    Cheng Cheng
    Deqing Pei
    Chunxu Qu
    Scott Newman
    Meenakshi Devidas
    Yunfeng Dai
    Shalini C. Reshmi
    Julie Gastier-Foster
    Elizabeth A. Raetz
    Michael J. Borowitz
    Brent L. Wood
    William L. Carroll
    Patrick A. Zweidler-McKay
    Karen R. Rabin
    Leonard A. Mattano
    Kelly W. Maloney
    Alessandro Rambaldi
    Orietta Spinelli
    Jerald P. Radich
    Mark D. Minden
    Jacob M. Rowe
    Selina Luger
    Mark R. Litzow
    Martin S. Tallman
    Janis Racevskis
    Yanming Zhang
    Ravi Bhatia
    Jessica Kohlschmidt
    Krzysztof Mrózek
    Clara D. Bloomfield
    Wendy Stock
    Steven Kornblau
    Hagop M. Kantarjian
    Marina Konopleva
    Williams E. Evans
    Nature Genetics, 2019, 51 : 296 - 307
  • [8] Characterization of PAX5-Driven Subtypes in B-Progenitor Acute Lymphoblastic Leukemia
    Gu, Z.
    Churchman, M.
    Moore, I.
    Roberts, K.
    Pelletier, S.
    Payne-Turner, D.
    Zhao, Y.
    Hill, A.
    Mullighan, C.
    PEDIATRIC BLOOD & CANCER, 2018, 65 : S65 - S66
  • [9] Characterization of PAX5-driven Subtypes in B-progenitor Acute Lymphoblastic Leukemia
    Gu, Zhaohui
    Churchman, Michelle
    Roberts, Kathryn
    Moore, Ian
    Zhou, Xin
    Nakitandwe, Joy
    Pelletier, Stephane
    Gingras, Sebastien
    Berns, Hartmut
    Payne-Turner, Debbie
    Hill, Ashley
    Iacobucci, Ilaria
    Hagiwara, Kohei
    Shi, Lei
    Pei, Deqing
    Qu, Chunxu
    Paietta, Elisabeth
    Pui, Ching-Hon
    Downing, James
    Loh, Mignon
    Hunger, Stephen
    Mullighan, Charles
    CLINICAL LYMPHOMA MYELOMA & LEUKEMIA, 2018, 18 : S183 - S183
  • [10] The Biology of B-Progenitor Acute Lymphoblastic Leukemia
    Roberts, Kathryn G.
    Mullighan, Charles G.
    COLD SPRING HARBOR PERSPECTIVES IN MEDICINE, 2020, 10 (07): : 1 - 22