title: Deregulated expression of the HSP40 family members Auxilin-1 and -2 is indicative of proteostasis imbalance and predicts patient outcome in Ph(+) leukemia.
abstract: BACKGROUND
  Proteostasis is defined by the orchestrated control of anabolic and catabolic protein pathways. Disruption of proteostasis results in cell stress and adaptation to proteostasis imbalance is mediated by adaptive pathways such as the Heat Shock Response (including heat-shock proteins) or the unfolded protein response (UPR). The BCR-ABL1 kinase (Philadelphia chromosome) is the hallmark of chronic myeloid leukemia (CML) and defines a historically poor subset in acute lymphoblastic leukemia (Ph(+) ALL). We previously demonstrated the importance of the UPR and particularly of the IRE1/XBP1 signaling axis in Ph(+) ALL, while others demonstrated the therapeutic relevance of HSP70 in ALL. In this regard, HSP70 is regulated by smaller HSP40 s, whose function is so far poorly characterized.
  
  
  RESULTS
  Herein, we characterize the expression of HSP40 s in Ph(+) ALL and CML. We show that these genes are not regulated in a pan-class manner and identify a homologous gene pair, namely Auxilin-1 (DNAJC6) and Auxilin-2 (GAK) with a unique expression profile. Overexpression of Auxilin-2, the ubiquitously expressed homologue of Auxilin-1 correlated with superior clinical outcome in ALL and was tightly linked to both IRE1 RNase and BCR-ABL1 kinase activities.
  
  
  CONCLUSIONS
  Our findings suggest that HSP40 gens are uniquely regulated and provide a rationale for further studies between BCR-ABL1/IRE1-based therapies in combination with HSP40 inhibitors, thus opening potentially novel therapeutic avenues.
authors: Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors: Margherita
authors: M
authors: Vieri
authors: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143 USA.
authors: Huimin
authors: H
authors: Geng
authors: MannKind Corporation, Valencia, CA USA.
authors: John B
authors: JB
authors: Patterson
authors: Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors: Jens
authors: J
authors: Panse
authors: Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors: Stefan
authors: S
authors: Wilop
authors: Apoptosis Research Centre, National University of Ireland, Galway, Ireland ; Department of Biochemistry, National University of Ireland, Galway, Ireland.
authors: Afshin
authors: A
authors: Samali
authors: INSERM ERL440, Oncogenesis, Stress and Signaling, Université Rennes 1, Rennes, France ; Centre de Lutte Contre Le Cancer Eugène Marquis, Rennes, France.
authors: Eric
authors: E
authors: Chevet
authors: Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors: Behzad
authors: B
authors: Kharabi Masouleh
keywords: Acute lymphoblastic leukemia; Auxilin-1; Auxilin-2; Chronic myeloid leukemia; DNAJ; HSP40; Unfolded protein response