Spred1 deficit promotes treatment resistance and transformation of chronic phase CML

Junjing Qiao, Chen Liang, Dandan Zhao, Le Xuan Truong Nguyen, Fang Chen, Shanshan Suo, Dinh Hoa Hoang, Francesca Pellicano, Ivan Rodriguez Rodriguez, Yasmin Elhajmoussa, Lucy Ghoda, Akihiko Yoshimura, Anthony S. Stein, Haris Ali, Paul Koller, Danilo Perrotti, Mhairi Copland, Anjia Han, Bin Zhang, Guido Marcucci

研究成果: Article査読

抄録

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 (LinSca-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. [Figure not available: see fulltext.]

本文言語English
ページ(範囲)492-506
ページ数15
ジャーナルLeukemia
36
2
DOI
出版ステータスPublished - 2022 2月

ASJC Scopus subject areas

  • 血液学
  • 腫瘍学
  • 癌研究

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