The core autophagy protein ATG4B is a potential biomarker and therapeutic target in CML stem/progenitor cells

Abstract

Key Points• The core autophagy protein ATG4B is highly expressed in CML stem/progenitor cells and may be useful in predicting treatment response.• ATG4B knockdown reduces autophagy, impairs the survival of CML stem/progenitor cells, and sensitizes them to IM treatment.Previous studies demonstrated that imatinib mesylate (IM) induces autophagy in chronic myeloid leukemia (CML) and that this process is critical to cell survival upon therapy. However, it is not known if the autophagic process differs at basal levels between CML patients and healthy individuals and if pretreatment CML cells harbor unique autophagy characteristics that could predict patients' clinical outcomes. We now demonstrate that several key autophagy genes are differentially expressed in CD34 1 hematopoietic stem/progenitor cells, with the highest transcript levels detected for ATG4B, and that the transcript and protein expression levels of ATG4 family members, ATG5 and BECLIN-1 are significantly increased in CD34 1 cells from chronicphase CML patients (P < .05). Importantly, ATG4B is differentially expressed in pretreatment CML stem/progenitor cells from subsequent IM responders vs IM nonresponders (P < .05). Knockdown of ATG4B suppresses autophagy, impairs the survival of CML stem/progenitor cells and sensitizes them to IM treatment. Moreover, deregulated expression of ATG4B in CD34 1 CML cells inversely correlates with transcript levels of miR-34a, and ATG4B is shown to be a direct target of miR-34a. This study identifies ATG4B as a potential biomarker for predicting therapeutic response in treatment-naïve CML stem/progenitor cells and uncovers ATG4B as a possible drug target in these cells. (Blood. 2014;123(23):3622-3634)

Role of autophagy in the maintenance and function of cancer stem cells

“…Both the survival of CML cells and leukemogenesis was shown to strictly rely on autophagy, as demonstrated in experiments performed by using the conditional knockout of ATG3 (Altman et al, 2011). The survival of CML stem/ progenitor cells was also impaired by the depletion of ATG4B (Rothe et al, 2014). Along similar lines, the inhibition of autophagy via the administration of chloroquine (CQ, a lysosomotropic agent arresting the fusion between autophagosomes and lysosomes (Firat et al, 2012, O'Donovan et al, 2011, Sasaki et al, 2010, Selvakumaran et al, 2013) depleted the CD44 + /CD24…”

“…This finding supports the use of DCLK1 as a potential target to sensitize tumors to curcumin. Finally, the depletion of autophagy by different approaches increased the cytotoxicity of the tyrosine kinase inhibitor imatinib or the AKT inhibitor perifosine (two drugs reported to activate autophagy) in CML cell lines (Bellodi et al, 2009, Elzinga et al, 2013, Rothe et al, 2014, Tong et al, 2012, Yu et al, 2012. On the other hand, the cytotoxic effect of some therapeutic agents is mediated by (and strictly requires) the molecular machinery of autophagy.…”

Intratumoral Heterogeneity: From Diversity Comes Resistance

“…þ CML stem cells have increased basal autophagy levels, and the CD34 þ cells in imatinib nonresponders have higher baseline autophagy than those of responders (59). Autophagy can serve as a resistance mechanism to these inhibitors, and cotreatment with an autophagy inhibitor sensitizes CML CSCs to imatinib (59,60).…”

The functional and pathologic relevance of autophagy proteases

“…Overexpression of an inactive mutant of ATG4B in hepatocellular carcinoma cells reduced their viability (112), and autophagy inhibition by miR-101, which targets ATG4D, enhanced cisplatin-induced apoptosis in these tumor cells (113). Disruption of the autophagic response has also been proposed as a therapeutic option in cisplatin-resistant patients with squamous cell carcinoma, in which ATG4A is upregulated (114), and chronic myeloid leukemia, in which ATG4B expression is involved in resistance of CD34 + cells to imatinib mesylate (66). Apart from the interest in ATG4 inhibition in cancer, a treatment based on the blockade of these proteases has also been suggested for type 1 diabetes mellitus, as some autophagic proteins (including ATG4A) could be related to neural injury of young patients with early neuronal deficits and diabetic ketoacidosis (115).…”

“…Notably, the activity of the different ATG4 family members can be fine-tuned by microRNAs after transcription. The tumor suppressor miR-101 inhibits autophagy by targeting ATG4D (64), miR-376b modulates human autophagy by regulating intracellular levels of ATG4C (65), and miR-34a targets ATG4B (66).…”