Abstract
The development of Imatinib mesylate (IM), which targets the oncogenic BCRABL fusion protein, has greatly improved the outcome of Chronic Myeloid Leukemia (CML) patients. However, BCR-ABL-positive progenitors can be detected in CML patients in complete cytogenetic response. Several evidence suggests that CML stem cells are intrinsically resistant to Tyrosine Kinase Inhibitors (TKI), and therefore they represent the most likely candidate responsible for disease relapse. In this work, we investigated the microRNA (miRNA) expression profile of different subpopulations of CML Leukemic Stem Cells (LSCs): Lin-CD34+CD38-and Lin-CD34-CD38-cells. These cell fractions have been previously shown to be endowed with TKI intrinsic resistance. Our analysis identified 33 common deregulated miRNAs in CML LSCs. Among those, 8 miRNAs were deregulated in CML independently from BCR-ABL kinase activity and therefore are likely to be involved in the BCR-ABL-independent resistance to TKI that characterizes CML LSCs. In particular, the up-regulation of miR-29a-3p and miR-660-5p observed in CML LSCs, led to the down-regulation of their respective targets TET2 and EPAS1 and conferred TKI-resistance to CML LSCs in vitro. On the other hand, miR-494-3p down-regulation in CML LSCs, leading to c-MYC up-regulation, was able to decrease TKI-induced apoptosis. These results demonstrate that aberrant miRNA expression in CML LSCs could contribute to the intrinsic TKIresistance observed in these cell populations, and support the development of novel therapies aimed at targeting aberrantly regulated miRNAs or their targets in order to effectively eradicate CML LSCs.
| Original language | English |
|---|---|
| Pages (from-to) | 49451-49469 |
| Number of pages | 19 |
| Journal | Oncotarget |
| Volume | 8 |
| Issue number | 30 |
| DOIs | |
| Publication status | Published - 2017 |
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Keywords
- Apoptosis
- Chronic myeloid leukemia
- Leukemic stem cells
- MicroRNAs
- Tyrosine kinase inhibitors
ASJC Scopus subject areas
- Oncology
Cite this
Deregulated expression of miR-29a-3p, miR-494-3p and miR-660-5p affects sensitivity to tyrosine kinase inhibitors in CML leukemic stem cells. / Salati, Simona; Salvestrini, Valentina; Carretta, Chiara; Genovese, Elena; Rontauroli, Sebastiano; Zini, Roberta; Rossi, Chiara; Ruberti, Samantha; Bianchi, Elisa; Barbieri, Greta; Curti, Antonio; Castagnetti, Fausto; Gugliotta, Gabriele; Rosti, Gianantonio; Bergamaschi, Micaela; Tafuri, Agostino; Tagliafico, Enrico; Lemoli, Roberto; Manfredini, Rossella.
In: Oncotarget, Vol. 8, No. 30, 2017, p. 49451-49469.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Deregulated expression of miR-29a-3p, miR-494-3p and miR-660-5p affects sensitivity to tyrosine kinase inhibitors in CML leukemic stem cells
AU - Salati, Simona
AU - Salvestrini, Valentina
AU - Carretta, Chiara
AU - Genovese, Elena
AU - Rontauroli, Sebastiano
AU - Zini, Roberta
AU - Rossi, Chiara
AU - Ruberti, Samantha
AU - Bianchi, Elisa
AU - Barbieri, Greta
AU - Curti, Antonio
AU - Castagnetti, Fausto
AU - Gugliotta, Gabriele
AU - Rosti, Gianantonio
AU - Bergamaschi, Micaela
AU - Tafuri, Agostino
AU - Tagliafico, Enrico
AU - Lemoli, Roberto
AU - Manfredini, Rossella
PY - 2017
Y1 - 2017
N2 - The development of Imatinib mesylate (IM), which targets the oncogenic BCRABL fusion protein, has greatly improved the outcome of Chronic Myeloid Leukemia (CML) patients. However, BCR-ABL-positive progenitors can be detected in CML patients in complete cytogenetic response. Several evidence suggests that CML stem cells are intrinsically resistant to Tyrosine Kinase Inhibitors (TKI), and therefore they represent the most likely candidate responsible for disease relapse. In this work, we investigated the microRNA (miRNA) expression profile of different subpopulations of CML Leukemic Stem Cells (LSCs): Lin-CD34+CD38-and Lin-CD34-CD38-cells. These cell fractions have been previously shown to be endowed with TKI intrinsic resistance. Our analysis identified 33 common deregulated miRNAs in CML LSCs. Among those, 8 miRNAs were deregulated in CML independently from BCR-ABL kinase activity and therefore are likely to be involved in the BCR-ABL-independent resistance to TKI that characterizes CML LSCs. In particular, the up-regulation of miR-29a-3p and miR-660-5p observed in CML LSCs, led to the down-regulation of their respective targets TET2 and EPAS1 and conferred TKI-resistance to CML LSCs in vitro. On the other hand, miR-494-3p down-regulation in CML LSCs, leading to c-MYC up-regulation, was able to decrease TKI-induced apoptosis. These results demonstrate that aberrant miRNA expression in CML LSCs could contribute to the intrinsic TKIresistance observed in these cell populations, and support the development of novel therapies aimed at targeting aberrantly regulated miRNAs or their targets in order to effectively eradicate CML LSCs.
AB - The development of Imatinib mesylate (IM), which targets the oncogenic BCRABL fusion protein, has greatly improved the outcome of Chronic Myeloid Leukemia (CML) patients. However, BCR-ABL-positive progenitors can be detected in CML patients in complete cytogenetic response. Several evidence suggests that CML stem cells are intrinsically resistant to Tyrosine Kinase Inhibitors (TKI), and therefore they represent the most likely candidate responsible for disease relapse. In this work, we investigated the microRNA (miRNA) expression profile of different subpopulations of CML Leukemic Stem Cells (LSCs): Lin-CD34+CD38-and Lin-CD34-CD38-cells. These cell fractions have been previously shown to be endowed with TKI intrinsic resistance. Our analysis identified 33 common deregulated miRNAs in CML LSCs. Among those, 8 miRNAs were deregulated in CML independently from BCR-ABL kinase activity and therefore are likely to be involved in the BCR-ABL-independent resistance to TKI that characterizes CML LSCs. In particular, the up-regulation of miR-29a-3p and miR-660-5p observed in CML LSCs, led to the down-regulation of their respective targets TET2 and EPAS1 and conferred TKI-resistance to CML LSCs in vitro. On the other hand, miR-494-3p down-regulation in CML LSCs, leading to c-MYC up-regulation, was able to decrease TKI-induced apoptosis. These results demonstrate that aberrant miRNA expression in CML LSCs could contribute to the intrinsic TKIresistance observed in these cell populations, and support the development of novel therapies aimed at targeting aberrantly regulated miRNAs or their targets in order to effectively eradicate CML LSCs.
KW - Apoptosis
KW - Chronic myeloid leukemia
KW - Leukemic stem cells
KW - MicroRNAs
KW - Tyrosine kinase inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85025842812&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85025842812&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.17706
DO - 10.18632/oncotarget.17706
M3 - Article
AN - SCOPUS:85025842812
VL - 8
SP - 49451
EP - 49469
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 30
ER -