Chronic Myeloid Leukemia Coverage from Every Angle
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Interaction of BCR-ABL and Beclin-1 in CML

By: Melissa E. Fryman, MS
Posted: Thursday, August 22, 2019

According to a study by Chuanjiang Yu, PhD, of the University Medical Center Freiburg, Germany, and colleagues, pathogenesis of chronic myeloid leukemia (CML) may be mediated by suppression of autophagy. Recent studies showing the involvement of autophagy in the CML treatment response have contained sparse in vivo data and did not elucidate precise molecular mechanisms. The present study, which was published in the journal Haematologica, highlights the role of the autophagy regulator Beclin-1 in CML.

“We show that BCR-ABL binds and phosphorylates Beclin-1 on tyrosine residues 233 and 352, thereby leading to alterations of the UVRAG-VPS15-ATG14-VPS34-Rubicon-Beclin-1 complex,” concluded the authors. “The BCR-ABL/Beclin-1 interaction suppresses autophagy and thereby bypasses the negative effect of autophagy on cancer cell survival and proliferation.”

The researchers used a combination of in vitro and in vivo models to dissect the role of autophagy mediators in CML progression. GST-pulldown assays, immunoprecipitation, and Western blotting were used to quantify levels of Beclin-1 and binding partners; kinase assays and flow cytometry were used to characterize phosphorylation and immune phenotype, respectively. BCR-ABL mice were studied to assess the effect of transplanted bone marrow derived cells with microRNA-based knockdown of Beclin-1.

Knockdown of Beclin-1 in BCR-ABL mice led to delayed leukemogenesis. Of interest, knockdown of another autophagy mediator, Atg5, did not achieve this effect. Nilotinib-based inhibition of BCR-ABL kinase activity led to increased autophagy, as measured by LC3 levels. BCR-ABL, but not other oncogenic kinases, uniquely phosphorylated Beclin-1. Consistent with this finding, Beclin-1 phosphorylation was confirmed in all primary CML samples tested, but not in control samples. Lastly, phosphomimetic-mutant Beclin-1 suppressed autophagy, whereas phosphodeficient-mutant Beclin-1 induced autophagy.

Disclosure: The study authors’ disclosure information may be found at haematologica.org.



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