Chemotherapeutic agents circumvent emergence of dasatinib-resistant BCR-ABL kinase mutations in a precise mouse model of Philadelphia chromosome-positive acute lymphoblastic leukemia
The introduction of cultured p185(BCR-ABL)-expressing (p185+) Arf (-/-) pre-B cells into healthy syngeneic mice induces aggressive acute lymphoblastic leukemia (ALL) that genetically and phenotypically mimics the human disease. We adapted this high-throughput Philadelphia chromosome-positive (Ph(+)) ALL animal model for in vivo luminescent imaging to investigate disease progression, targeted therapeutic response, and ALL relapse in living mice. Mice bearing high leukemic burdens (simulating human Ph(+) ALL at diagnosis) entered remission on maximally intensive, twice-daily dasatinib therapy, but invariably relapsed with disseminated and/or central nervous system disease. Although relapse was frequently accompanied by the eventual appearance of leukemic clones harboring BCR-ABL kinase domain (KD) mutations that confer drug resistance, their clonal emergence required prolonged dasatinib exposure. KD P-loop mutations predominated in mice receiving less intensive therapy, whereas high-dose treatment selected for T315I "gatekeeper" mutations resistant to all 3 Food and Drug Administration-approved BCR-ABL kinase inhibitors. The addition of dexamethasone and/or L-asparaginase to reduced-intensity dasatinib therapy improved long-term survival of the majority of mice that received all 3 drugs. Although non-tumor-cell-autonomous mechanisms can prevent full eradication of dasatinib-refractory ALL in this clinically relevant model, the emergence of resistance to BCR-ABL kinase inhibitors can be effectively circumvented by the addition of "conventional" chemotherapeutic agents with alternate antileukemic mechanisms of action.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2011 |
|---|---|
| Erschienen: |
2011 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:117 |
|---|---|
| Enthalten in: |
Blood - 117(2011), 13 vom: 31. März, Seite 3585-95 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Boulos, Nidal [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 02.06.2011 Date Revised 20.10.2021 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1182/blood-2010-08-301267 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM205319408 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM205319408 | ||
| 003 | DE-627 | ||
| 005 | 20231223233720.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231223s2011 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1182/blood-2010-08-301267 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0684.xml |
| 035 | |a (DE-627)NLM205319408 | ||
| 035 | |a (NLM)21263154 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Boulos, Nidal |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Chemotherapeutic agents circumvent emergence of dasatinib-resistant BCR-ABL kinase mutations in a precise mouse model of Philadelphia chromosome-positive acute lymphoblastic leukemia |
| 264 | 1 | |c 2011 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 02.06.2011 | ||
| 500 | |a Date Revised 20.10.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a The introduction of cultured p185(BCR-ABL)-expressing (p185+) Arf (-/-) pre-B cells into healthy syngeneic mice induces aggressive acute lymphoblastic leukemia (ALL) that genetically and phenotypically mimics the human disease. We adapted this high-throughput Philadelphia chromosome-positive (Ph(+)) ALL animal model for in vivo luminescent imaging to investigate disease progression, targeted therapeutic response, and ALL relapse in living mice. Mice bearing high leukemic burdens (simulating human Ph(+) ALL at diagnosis) entered remission on maximally intensive, twice-daily dasatinib therapy, but invariably relapsed with disseminated and/or central nervous system disease. Although relapse was frequently accompanied by the eventual appearance of leukemic clones harboring BCR-ABL kinase domain (KD) mutations that confer drug resistance, their clonal emergence required prolonged dasatinib exposure. KD P-loop mutations predominated in mice receiving less intensive therapy, whereas high-dose treatment selected for T315I "gatekeeper" mutations resistant to all 3 Food and Drug Administration-approved BCR-ABL kinase inhibitors. The addition of dexamethasone and/or L-asparaginase to reduced-intensity dasatinib therapy improved long-term survival of the majority of mice that received all 3 drugs. Although non-tumor-cell-autonomous mechanisms can prevent full eradication of dasatinib-refractory ALL in this clinically relevant model, the emergence of resistance to BCR-ABL kinase inhibitors can be effectively circumvented by the addition of "conventional" chemotherapeutic agents with alternate antileukemic mechanisms of action | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Cdkn2a protein, mouse |2 NLM | |
| 650 | 7 | |a Cyclin-Dependent Kinase Inhibitor p16 |2 NLM | |
| 650 | 7 | |a Pyrimidines |2 NLM | |
| 650 | 7 | |a Thiazoles |2 NLM | |
| 650 | 7 | |a Fusion Proteins, bcr-abl |2 NLM | |
| 650 | 7 | |a EC 2.7.10.2 |2 NLM | |
| 650 | 7 | |a Dasatinib |2 NLM | |
| 650 | 7 | |a RBZ1571X5H |2 NLM | |
| 700 | 1 | |a Mulder, Heather L |e verfasserin |4 aut | |
| 700 | 1 | |a Calabrese, Christopher R |e verfasserin |4 aut | |
| 700 | 1 | |a Morrison, Jeffrey B |e verfasserin |4 aut | |
| 700 | 1 | |a Rehg, Jerold E |e verfasserin |4 aut | |
| 700 | 1 | |a Relling, Mary V |e verfasserin |4 aut | |
| 700 | 1 | |a Sherr, Charles J |e verfasserin |4 aut | |
| 700 | 1 | |a Williams, Richard T |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Blood |d 1946 |g 117(2011), 13 vom: 31. März, Seite 3585-95 |w (DE-627)NLM000014761 |x 1528-0020 |7 nnns |
| 773 | 1 | 8 | |g volume:117 |g year:2011 |g number:13 |g day:31 |g month:03 |g pages:3585-95 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1182/blood-2010-08-301267 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 117 |j 2011 |e 13 |b 31 |c 03 |h 3585-95 | ||