PMID- 34406033
OWN - NLM
STAT- MEDLINE
DCOM- 20220111
LR  - 20220111
IS  - 2573-1602 (Electronic)
IS  - 2573-1599 (Linking)
VI  - 4
IP  - 4
DP  - 2021 Aug
TI  - CRISPR-Cas9 Technology as a Tool to Target Gene Drivers in Cancer: Proof of 
      Concept and New Opportunities to Treat Chronic Myeloid Leukemia.
PG  - 519-535
LID - 10.1089/crispr.2021.0009 [doi]
AB  - Chronic myeloid leukemia (CML) is a hematopoietic malignancy produced by a unique 
      oncogenic event involving the constitutively active tyrosine-kinase (TK) 
      BCR/ABL1. TK inhibitors (TKI) changed its prognosis and natural history. 
      Unfortunately, ABL1 remains unaffected by TKIs. Leukemic stem cells (LSCs) 
      remain, and resistant mutations arise during treatment. To address this problem, 
      we have designed a therapeutic CRISPR-Cas9 deletion system targeting BCR/ABL1. 
      The system was efficiently electroporated to cell lines, LSCs from a CML murine 
      model, and LSCs from CML patients at diagnosis, generating a specific ABL1 null 
      mutation at high efficiency and allowing the edited leukemic cells to be detected 
      and tracked. The CRISPR-Cas9 deletion system triggered cell proliferation arrest 
      and apoptosis in murine and human CML cell lines. Patient and murine-derived 
      xenografts with CRISPR-edited LSCs in NOD SCID gamma niches revealed that normal 
      multipotency and repopulation ability of CRISPR edited LSCs were fully restored. 
      Normal hematopoiesis was restored, avoiding myeloid bias. To the best of our 
      knowledge, we show for the first time how a CRISPR-Cas9 deletion system 
      efficiently interrupts BCR/ABL1 oncogene in primary LSCs to bestow a therapeutic 
      benefit. This study is a proof of concept for genome editing in all those 
      diseases, like CML, sustained by a single oncogenic event, opening up new 
      therapeutic opportunities.
FAU - Vuelta, Elena
AU  - Vuelta E
AD  - Unidad de Diagnostico Molecular y Celular del Cancer, Instituto Biologia 
      Molecular y Celular del Cancer (USAL/CSIC), Salamanca, Spain; Hospital 
      Universitario de Salamanca, Salamanca, Spain.
AD  - Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain; Hospital 
      Universitario de Salamanca, Salamanca, Spain.
AD  - Servicio de Transgenesis, NUCLEUS, Universidad de Salamanca, Salamanca, Spain; 
      Hospital Universitario de Salamanca, Salamanca, Spain.
FAU - Ordonez, Jose Luis
AU  - Ordonez JL
AD  - Unidad de Diagnostico Molecular y Celular del Cancer, Instituto Biologia 
      Molecular y Celular del Cancer (USAL/CSIC), Salamanca, Spain; Hospital 
      Universitario de Salamanca, Salamanca, Spain.
AD  - IBSAL, Instituto de Investigacion Biomedica de Salamanca, Salamanca, Spain; 
      Hospital Universitario de Salamanca, Salamanca, Spain.
FAU - Alonso-Perez, Veronica
AU  - Alonso-Perez V
AD  - Unidad de Diagnostico Molecular y Celular del Cancer, Instituto Biologia 
      Molecular y Celular del Cancer (USAL/CSIC), Salamanca, Spain; Hospital 
      Universitario de Salamanca, Salamanca, Spain.
AD  - IBSAL, Instituto de Investigacion Biomedica de Salamanca, Salamanca, Spain; 
      Hospital Universitario de Salamanca, Salamanca, Spain.
FAU - Mendez, Lucia
AU  - Mendez L
AD  - Servicio de Transgenesis, NUCLEUS, Universidad de Salamanca, Salamanca, Spain; 
      Hospital Universitario de Salamanca, Salamanca, Spain.
FAU - Hernandez-Carabias, Patricia
AU  - Hernandez-Carabias P
AD  - Servicio de Transgenesis, NUCLEUS, Universidad de Salamanca, Salamanca, Spain; 
      Hospital Universitario de Salamanca, Salamanca, Spain.
FAU - Saldana, Raquel
AU  - Saldana R
AD  - Servicio de Hematologia, Hospital de Jerez, Cadiz, Spain; Hospital Universitario 
      de Salamanca, Salamanca, Spain.
FAU - Sevilla, Julian
AU  - Sevilla J
AD  - Hospital Infantil Universitario Nino Jesus, Madrid, Spain; Hospital Universitario 
      de Salamanca, Salamanca, Spain.
FAU - Sebastian, Elena
AU  - Sebastian E
AD  - Hospital Infantil Universitario Nino Jesus, Madrid, Spain; Hospital Universitario 
      de Salamanca, Salamanca, Spain.
FAU - Muntion, Sandra
AU  - Muntion S
AD  - Unidad de Diagnostico Molecular y Celular del Cancer, Instituto Biologia 
      Molecular y Celular del Cancer (USAL/CSIC), Salamanca, Spain; Hospital 
      Universitario de Salamanca, Salamanca, Spain.
AD  - Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain; Hospital 
      Universitario de Salamanca, Salamanca, Spain.
AD  - Hospital Infantil Universitario Nino Jesus, Madrid, Spain; Hospital Universitario 
      de Salamanca, Salamanca, Spain.
AD  - RETIC TerCel y CIBERONC, ISCIII, Madrid, Spain; and Hospital Universitario de 
      Salamanca, Salamanca, Spain.
AD  - Servicio de Hematologia, Hospital Universitario de Salamanca, Salamanca, Spain.
FAU - Sanchez-Guijo, Fermin
AU  - Sanchez-Guijo F
AD  - Unidad de Diagnostico Molecular y Celular del Cancer, Instituto Biologia 
      Molecular y Celular del Cancer (USAL/CSIC), Salamanca, Spain; Hospital 
      Universitario de Salamanca, Salamanca, Spain.
AD  - Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain; Hospital 
      Universitario de Salamanca, Salamanca, Spain.
AD  - Hospital Infantil Universitario Nino Jesus, Madrid, Spain; Hospital Universitario 
      de Salamanca, Salamanca, Spain.
AD  - RETIC TerCel y CIBERONC, ISCIII, Madrid, Spain; and Hospital Universitario de 
      Salamanca, Salamanca, Spain.
AD  - Servicio de Hematologia, Hospital Universitario de Salamanca, Salamanca, Spain.
FAU - Hernandez-Rivas, Jesus Maria
AU  - Hernandez-Rivas JM
AD  - Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain; Hospital 
      Universitario de Salamanca, Salamanca, Spain.
AD  - IBSAL, Instituto de Investigacion Biomedica de Salamanca, Salamanca, Spain; 
      Hospital Universitario de Salamanca, Salamanca, Spain.
AD  - Servicio de Hematologia, Hospital Universitario de Salamanca, Salamanca, Spain.
FAU - Garcia-Tunon, Ignacio
AU  - Garcia-Tunon I
AD  - Unidad de Diagnostico Molecular y Celular del Cancer, Instituto Biologia 
      Molecular y Celular del Cancer (USAL/CSIC), Salamanca, Spain; Hospital 
      Universitario de Salamanca, Salamanca, Spain.
AD  - IBSAL, Instituto de Investigacion Biomedica de Salamanca, Salamanca, Spain; 
      Hospital Universitario de Salamanca, Salamanca, Spain.
FAU - Sanchez-Martin, Manuel
AU  - Sanchez-Martin M
AD  - Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain; Hospital 
      Universitario de Salamanca, Salamanca, Spain.
AD  - Servicio de Transgenesis, NUCLEUS, Universidad de Salamanca, Salamanca, Spain; 
      Hospital Universitario de Salamanca, Salamanca, Spain.
AD  - IBSAL, Instituto de Investigacion Biomedica de Salamanca, Salamanca, Spain; 
      Hospital Universitario de Salamanca, Salamanca, Spain.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - CRISPR J
JT  - The CRISPR journal
JID - 101738191
RN  - EC 2.7.10.2 (Fusion Proteins, bcr-abl)
SB  - IM
MH  - Animals
MH  - *CRISPR-Cas Systems
MH  - Cell Line, Tumor
MH  - Disease Models, Animal
MH  - Fusion Proteins, bcr-abl/genetics
MH  - *Gene Editing
MH  - Gene Expression
MH  - Gene Targeting/methods
MH  - Gene Transfer Techniques
MH  - *Genetic Therapy/methods
MH  - Hematopoiesis/genetics
MH  - Hematopoietic Stem Cell Transplantation
MH  - Hematopoietic Stem Cells/cytology/metabolism
MH  - Heterografts
MH  - Humans
MH  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*genetics/therapy
MH  - Mice
MH  - Neoplastic Stem Cells/metabolism
MH  - *Oncogenes
MH  - Proof of Concept Study
EDAT- 2021/08/19 06:00
MHDA- 2022/01/12 06:00
CRDT- 2021/08/18 12:15
PHST- 2021/08/18 12:15 [entrez]
PHST- 2021/08/19 06:00 [pubmed]
PHST- 2022/01/12 06:00 [medline]
AID - 10.1089/crispr.2021.0009 [doi]
PST - ppublish
SO  - CRISPR J. 2021 Aug;4(4):519-535. doi: 10.1089/crispr.2021.0009.