In Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities.
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.
Pubmed ID: 36468984 RIS Download
Research resources used in this publication
- TNFRSF8/CD30 (E4L4I) XP® Rabbit mAb (RRID:AB_2799462) (antibody)
- GAPDH (D16H11) XP® Rabbit mAb (HRP Conjugate) (RRID:AB_11129865) (antibody)
- c-Myc antibody [Y69] (RRID:AB_731658) (antibody)
- IRF-4 (E8H3S) XP® Rabbit mAb (RRID:AB_2877647) (antibody)
- Ki-67 (D3B5) Rabbit mAb (Mouse Preferred; IHC Formulated) (RRID:AB_2620142) (antibody)
- PAX5 (D7H5X) XP® Rabbit mAb (RRID:AB_2798001) (antibody)
- PTEN (D4.3) XP Rabbit mAb (RRID:AB_2253290) (antibody)
- Rabbit Anti-SHP-1 Monoclonal Antibody, Unconjugated, Clone C14H6 (RRID:AB_2173694) (antibody)
- Stat3 (D3Z2G) Rabbit mAb #12640 (RRID:AB_2629499) (antibody)
- Phospho-p70 S6 Kinase (Thr389) (D5U1O) Rabbit mAb (RRID:AB_2800283) (antibody)
- Phospho-Akt (Ser473) (D9E) XP® Rabbit mAb (RRID:AB_2315049) (antibody)
- Phospho-Stat3 (Tyr705) (D3A7) XP Rabbit mAb (RRID:AB_2491009) (antibody)
- Rabbit Anti-Stat1, phospho (Tyr701) Monoclonal Antibody, Unconjugated, Clone 58D6 (RRID:AB_561284) (antibody)
- PerCP/Cy5.5 Rat IgG2b, kappa Isotype Ctrl (RRID:AB_893677) (antibody)
- Brilliant Violet 510™ Mouse IgG2a, κ Isotype Ctrl Antibody (RRID:AB_2734131) (antibody)
- PerCP/Cyanine5.5 anti-mouse I-A/I-E (RRID:AB_2191071) (antibody)
- Brilliant Violet 510(TM) anti-mouse H-2Kb (RRID:AB_2800584) (antibody)
- Alexa Fluor(R) 700 anti-mouse Ig light chain kappa (RRID:AB_2563583) (antibody)
- PE/Cyanine7 anti-mouse CD5 (RRID:AB_2562773) (antibody)
- APC/Cyanine7 anti-mouse CD3 (RRID:AB_2242784) (antibody)
- APC anti-mouse/human CD11b (RRID:AB_312795) (antibody)
- Pacific Blue(TM) anti-mouse/human CD45R/B220 (RRID:AB_492876) (antibody)
- Brilliant Violet 711(TM) anti-mouse CD45.2 (RRID:AB_2616859) (antibody)
- APC anti-mouse CD117 (c-kit) (RRID:AB_313221) (antibody)
- PE anti-mouse Ly-6A/E (Sca-1) (RRID:AB_313345) (antibody)
- Pacific Blue anti-mouse Lineage Cocktail (RRID:AB_11150779) (antibody)
Additional research tools detected in this publication
None foundAntibodies used in this publication
- GAPDH (D16H11) XP® Rabbit mAb (HRP Conjugate) (RRID:AB_11129865)
- Rabbit Anti-SHP-1 Monoclonal Antibody, Unconjugated, Clone C14H6 (RRID:AB_2173694)
- TNFRSF8/CD30 (E4L4I) XP® Rabbit mAb (RRID:AB_2799462)
- c-Myc antibody [Y69] (RRID:AB_731658)
- IRF-4 (E8H3S) XP® Rabbit mAb (RRID:AB_2877647)
- Ki-67 (D3B5) Rabbit mAb (Mouse Preferred; IHC Formulated) (RRID:AB_2620142)
- PAX5 (D7H5X) XP® Rabbit mAb (RRID:AB_2798001)
- PTEN (D4.3) XP Rabbit mAb (RRID:AB_2253290)
- c-Myc (D84C12) XP Rabbit mAb (RRID:AB_1903938)
- Akt Antibody (RRID:AB_329827)
- Stat3 (D3Z2G) Rabbit mAb #12640 (RRID:AB_2629499)
- Phospho-p70 S6 Kinase (Thr389) (D5U1O) Rabbit mAb (RRID:AB_2800283)
- Phospho-Akt (Ser473) (D9E) XP® Rabbit mAb (RRID:AB_2315049)
- Phospho-Stat3 (Tyr705) (D3A7) XP Rabbit mAb (RRID:AB_2491009)
- Rabbit Anti-Stat1, phospho (Tyr701) Monoclonal Antibody, Unconjugated, Clone 58D6 (RRID:AB_561284)
- PerCP/Cy5.5 Rat IgG2b, kappa Isotype Ctrl (RRID:AB_893677)
- Brilliant Violet 510™ Mouse IgG2a, κ Isotype Ctrl Antibody (RRID:AB_2734131)
- PerCP/Cyanine5.5 anti-mouse I-A/I-E (RRID:AB_2191071)
- Brilliant Violet 510(TM) anti-mouse H-2Kb (RRID:AB_2800584)
- Alexa Fluor(R) 700 anti-mouse Ig light chain kappa (RRID:AB_2563583)
- PE/Cyanine7 anti-mouse CD5 (RRID:AB_2562773)
- APC/Cyanine7 anti-mouse CD3 (RRID:AB_2242784)
- APC anti-mouse/human CD11b (RRID:AB_312795)
- Pacific Blue(TM) anti-mouse/human CD45R/B220 (RRID:AB_492876)
- Brilliant Violet 711(TM) anti-mouse CD45.2 (RRID:AB_2616859)
- APC anti-mouse CD117 (c-kit) (RRID:AB_313221)
- PE anti-mouse Ly-6A/E (Sca-1) (RRID:AB_313345)
- Pacific Blue anti-mouse Lineage Cocktail (RRID:AB_11150779)
- Rabbit Anti-p70 S6 Kinase Monoclonal Antibody, Unconjugated, Clone 49D7 (RRID:AB_390722)
Associated grants
- Agency: NCI NIH HHS, United States
Id: R50 CA251956 - Agency: NCI NIH HHS, United States
Id: P01 CA206978 - Agency: NCI NIH HHS, United States
Id: R21 CA267527
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This is a list of tools and resources that we have found mentioned in this publication.
GAPDH (D16H11) XP® Rabbit mAb (HRP Conjugate) (antibody)
RRID:AB_11129865
This unknown targets GAPDH (D16H11) XP® Rabbit mAb (HRP Conjugate)
View all literature mentionsRabbit Anti-SHP-1 Monoclonal Antibody, Unconjugated, Clone C14H6 (antibody)
RRID:AB_2173694
This monoclonal targets PTPN6
View all literature mentionsTNFRSF8/CD30 (E4L4I) XP® Rabbit mAb (antibody)
RRID:AB_2799462
This monoclonal targets TNFRSF8
View all literature mentionsc-Myc antibody [Y69] (antibody)
RRID:AB_731658
This monoclonal targets c-Myc antibody [Y69]
View all literature mentionsIRF-4 (E8H3S) XP® Rabbit mAb (antibody)
RRID:AB_2877647
This monoclonal targets IRF-4
View all literature mentionsKi-67 (D3B5) Rabbit mAb (Mouse Preferred; IHC Formulated) (antibody)
RRID:AB_2620142
This monoclonal targets Ki-67
View all literature mentionsPAX5 (D7H5X) XP® Rabbit mAb (antibody)
RRID:AB_2798001
This monoclonal targets PAX5
View all literature mentionsPTEN (D4.3) XP Rabbit mAb (antibody)
RRID:AB_2253290
This monoclonal targets PTEN (D4.3) XP Rabbit mAb
View all literature mentionsc-Myc (D84C12) XP Rabbit mAb (antibody)
RRID:AB_1903938
This monoclonal targets c-Myc (D84C12) XP Rabbit mAb
View all literature mentionsStat3 (D3Z2G) Rabbit mAb #12640 (antibody)
RRID:AB_2629499
This monoclonal targets Human, Mouse, Rat, Monkey
View all literature mentionsPhospho-p70 S6 Kinase (Thr389) (D5U1O) Rabbit mAb (antibody)
RRID:AB_2800283
This monoclonal targets p70S6K
View all literature mentionsPhospho-Akt (Ser473) (D9E) XP® Rabbit mAb (antibody)
RRID:AB_2315049
This monoclonal targets Phospho-Akt (Ser473)
View all literature mentionsPhospho-Stat3 (Tyr705) (D3A7) XP Rabbit mAb (antibody)
RRID:AB_2491009
This monoclonal targets Phospho-Stat3 (Tyr705)
View all literature mentionsRabbit Anti-Stat1, phospho (Tyr701) Monoclonal Antibody, Unconjugated, Clone 58D6 (antibody)
RRID:AB_561284
This monoclonal targets Stat1, phospho (Tyr701)
View all literature mentionsPerCP/Cy5.5 Rat IgG2b, kappa Isotype Ctrl (antibody)
RRID:AB_893677
This unknown targets Rat IgG2b k Isotype Control PerCP / Cy5.5 Clone RTK4530
View all literature mentionsBrilliant Violet 510™ Mouse IgG2a, κ Isotype Ctrl Antibody (antibody)
RRID:AB_2734131
This isotype control targets
View all literature mentionsPerCP/Cyanine5.5 anti-mouse I-A/I-E (antibody)
RRID:AB_2191071
This monoclonal targets I-A/I-E
View all literature mentionsBrilliant Violet 510(TM) anti-mouse H-2Kb (antibody)
RRID:AB_2800584
This monoclonal targets H-2Kb
View all literature mentionsAlexa Fluor(R) 700 anti-mouse Ig light chain kappa (antibody)
RRID:AB_2563583
This monoclonal targets Ig light chain kappa
View all literature mentionsPE/Cyanine7 anti-mouse CD5 (antibody)
RRID:AB_2562773
This monoclonal targets CD5
View all literature mentionsAPC/Cyanine7 anti-mouse CD3 (antibody)
RRID:AB_2242784
This monoclonal targets CD3
View all literature mentionsAPC anti-mouse/human CD11b (antibody)
RRID:AB_312795
This monoclonal targets CD11b
View all literature mentionsPacific Blue(TM) anti-mouse/human CD45R/B220 (antibody)
RRID:AB_492876
This monoclonal targets CD45R
View all literature mentionsBrilliant Violet 711(TM) anti-mouse CD45.2 (antibody)
RRID:AB_2616859
This monoclonal targets CD45.2
View all literature mentionsAPC anti-mouse CD117 (c-kit) (antibody)
RRID:AB_313221
This monoclonal targets CD117
View all literature mentionsPE anti-mouse Ly-6A/E (Sca-1) (antibody)
RRID:AB_313345
This monoclonal targets Ly-6A/E
View all literature mentionsPacific Blue anti-mouse Lineage Cocktail (antibody)
RRID:AB_11150779
This monoclonal targets Pacific Blue anti-mouse Lineage Cocktail
View all literature mentionsRabbit Anti-p70 S6 Kinase Monoclonal Antibody, Unconjugated, Clone 49D7 (antibody)
RRID:AB_390722
This monoclonal targets p70 S6 Kinase
View all literature mentionsTNFRSF8/CD30 (E4L4I) XP® Rabbit mAb (antibody)
RRID:AB_2799462
This monoclonal targets TNFRSF8
View all literature mentionsGAPDH (D16H11) XP® Rabbit mAb (HRP Conjugate) (antibody)
RRID:AB_11129865
This unknown targets GAPDH (D16H11) XP® Rabbit mAb (HRP Conjugate)
View all literature mentionsc-Myc antibody [Y69] (antibody)
RRID:AB_731658
This monoclonal targets c-Myc antibody [Y69]
View all literature mentionsIRF-4 (E8H3S) XP® Rabbit mAb (antibody)
RRID:AB_2877647
This monoclonal targets IRF-4
View all literature mentionsKi-67 (D3B5) Rabbit mAb (Mouse Preferred; IHC Formulated) (antibody)
RRID:AB_2620142
This monoclonal targets Ki-67
View all literature mentionsPAX5 (D7H5X) XP® Rabbit mAb (antibody)
RRID:AB_2798001
This monoclonal targets PAX5
View all literature mentionsPTEN (D4.3) XP Rabbit mAb (antibody)
RRID:AB_2253290
This monoclonal targets PTEN (D4.3) XP Rabbit mAb
View all literature mentionsRabbit Anti-SHP-1 Monoclonal Antibody, Unconjugated, Clone C14H6 (antibody)
RRID:AB_2173694
This monoclonal targets PTPN6
View all literature mentionsStat3 (D3Z2G) Rabbit mAb #12640 (antibody)
RRID:AB_2629499
This monoclonal targets Human, Mouse, Rat, Monkey
View all literature mentionsPhospho-p70 S6 Kinase (Thr389) (D5U1O) Rabbit mAb (antibody)
RRID:AB_2800283
This monoclonal targets p70S6K
View all literature mentionsPhospho-Akt (Ser473) (D9E) XP® Rabbit mAb (antibody)
RRID:AB_2315049
This monoclonal targets Phospho-Akt (Ser473)
View all literature mentionsPhospho-Stat3 (Tyr705) (D3A7) XP Rabbit mAb (antibody)
RRID:AB_2491009
This monoclonal targets Phospho-Stat3 (Tyr705)
View all literature mentionsRabbit Anti-Stat1, phospho (Tyr701) Monoclonal Antibody, Unconjugated, Clone 58D6 (antibody)
RRID:AB_561284
This monoclonal targets Stat1, phospho (Tyr701)
View all literature mentionsPerCP/Cy5.5 Rat IgG2b, kappa Isotype Ctrl (antibody)
RRID:AB_893677
This unknown targets Rat IgG2b k Isotype Control PerCP / Cy5.5 Clone RTK4530
View all literature mentionsBrilliant Violet 510™ Mouse IgG2a, κ Isotype Ctrl Antibody (antibody)
RRID:AB_2734131
This isotype control targets
View all literature mentionsPerCP/Cyanine5.5 anti-mouse I-A/I-E (antibody)
RRID:AB_2191071
This monoclonal targets I-A/I-E
View all literature mentionsBrilliant Violet 510(TM) anti-mouse H-2Kb (antibody)
RRID:AB_2800584
This monoclonal targets H-2Kb
View all literature mentionsAlexa Fluor(R) 700 anti-mouse Ig light chain kappa (antibody)
RRID:AB_2563583
This monoclonal targets Ig light chain kappa
View all literature mentionsPE/Cyanine7 anti-mouse CD5 (antibody)
RRID:AB_2562773
This monoclonal targets CD5
View all literature mentionsAPC/Cyanine7 anti-mouse CD3 (antibody)
RRID:AB_2242784
This monoclonal targets CD3
View all literature mentionsAPC anti-mouse/human CD11b (antibody)
RRID:AB_312795
This monoclonal targets CD11b
View all literature mentionsPacific Blue(TM) anti-mouse/human CD45R/B220 (antibody)
RRID:AB_492876
This monoclonal targets CD45R
View all literature mentionsBrilliant Violet 711(TM) anti-mouse CD45.2 (antibody)
RRID:AB_2616859
This monoclonal targets CD45.2
View all literature mentionsAPC anti-mouse CD117 (c-kit) (antibody)
RRID:AB_313221
This monoclonal targets CD117
View all literature mentionsPE anti-mouse Ly-6A/E (Sca-1) (antibody)
RRID:AB_313345
This monoclonal targets Ly-6A/E
View all literature mentionsPacific Blue anti-mouse Lineage Cocktail (antibody)
RRID:AB_11150779
This monoclonal targets Pacific Blue anti-mouse Lineage Cocktail
View all literature mentions
