Spred1 deficit promotes treatment resistance and transformation of chronic phase CML.
Leukemia
; 36(2): 492-506, 2022 02.
Article
em En
| MEDLINE
| ID: mdl-34564700
ABSTRACT
Spred1 is highly expressed in normal hematopoietic stem cells (HSCs). Lack of Spred1 function has been associated with aberrant hematopoiesis and acute leukemias. In chronic myelogenous leukemia (CML), Spred1 is reduced in patients with accelerated phase (AP) or blast crisis (BC) CML, thereby suggesting that deficit of this protein may contribute to disease transformation. In fact, Spred1 knockout (KO) in SCLtTA/BCR-ABL CML mice either globally, or restricted to hematopoietic cells (i.e., HSCs) or to endothelial cells (ECs), led to transformation of chronic phase (CP) CML into AP/BC CML. Upon BCR-ABL induction, all three Spred1 KO CML models showed AP/BC features. However, compared with global Spred1 KO, the AP/BC phenotypes of HSC-Spred1 KO and EC-Spred1 KO CML models were attenuated, suggesting a concurrent contribution of Spred1 deficit in multiple compartments of the leukemic bone marrow niche to the CML transformation. Spred1 KO, regardless if occurred in HSCs or in ECs, increased miR-126 in LSKs (Lin-Sca-1+c-Kit+), a population enriched in leukemic stem cells (LSCs), resulting in expansion of LSCs, likely through hyperactivation of the MAPK/ERK pathway that augmented Bcl-2 expression and stability. This ultimately led to enhancement of Bcl-2-dependent oxidative phosphorylation that supported homeostasis, survival and activity of LSCs and drove AP/BC transformation.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Neoplásicas
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Células-Tronco Hematopoéticas
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Leucemia Mielogênica Crônica BCR-ABL Positiva
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Transformação Celular Neoplásica
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Resistencia a Medicamentos Antineoplásicos
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Proteínas Adaptadoras de Transdução de Sinal
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article