Bcr-abl signals to desensitize chronic myeloid leukemia cells to IFNα via accelerating the degradation of its receptor

Abstract

IntroductionPatients with chronic myeloid leukemia (CML) harbor a specific translocation t(9;22)(q34;q11), the Philadelphia chromosome, resulting in the expression of a constitutively active protein tyrosine kinase Bcr-abl that is essential for the hematopoietic cell transformation. 1 This kinase exerts its oncogenic function by activating a cascade of intracellular signaling pathways that lead to increased cell survival and proliferation and limited dependence on growth factors. Among these pathways are those that mediate activation of PI3K-Akt, MAPK, and protein kinase (PK)C/PKD signaling cascades that generally stimulate cell proliferation and survival. 2,3 The Bcr-abl inhibitor imatinib mesylate (IM) has replaced interferon IFN␣ as the standard of care for patients with newly diagnosed chronic myeloid leukemia (CML) because of higher response frequency, substantially superior molecular and cytogenetic responses, lesser toxicity, and better survival. [4][5][6][7] Yet, although rapidly killing differentiated CML cells, IM is less efficient against more primitive leukemic stem cells and early progenitor cells. 8,9 Thus, patients receiving IM are not cured and require life-long treatment that is often compromised by resistance to IM because of mutations in Bcr-abl tyrosine kinase. 7,10 The ability of the second and third generation of tyrosine kinase inhibitors (TKIs; eg, dasatinib that might be active against mutant kinases) to eradicate quiescent early CML progenitors remains to be determined. 11 It is plausible that a combination of Bcr-abl inhibitors and the agents targeting the leukemic stem cell population might be required to eradicate the disease in CML patients.Recent evidence suggests that leukemic stem cells might undergo terminal differentiation in response to IFN␣, 12 a cytokine known to produce a curative effect in a small subset of patients (reviewed in Kujawski and Talpaz 13 ). Although these results, along with reports on several cases of successful treatment with IFN␣ after a course of IM (or vice versa), 14,15 provide new enthusiasm for the reintroduction of IFN␣ into the management of CML, 13 the molecular mechanisms that underlie the rationale for combining Bcr-abl inhibitors and IFN␣ remain to be delineated. Cellular responses to IFN␣ are mediated by the cell surface type I IFN receptor that consists of the interferon-␣/␤ receptor (IFNAR)1 and IFNAR2 chains. Ligand-stimulated dimerization of these chains leads to the activation of Janus kinase (JAK) family members JAK1 and TYK2. JAK1 and TYK2 phosphorylate signal transducers and activators of transcription (STAT) family proteins at specific tyrosine residues. Tyrosine phosphorylation of STAT1 and STAT2 along with subsequent recruitment of p48/IRF9 leads to the formation of a potent transcription factor that transactivates IFN-stimulated genes and contribute to the antiproliferative effects of IFN␣ (for reviews, see [16][17][18][19] ).A better understanding of molecular interactions between IFN␣-and Bcr-abl-induced signaling pathways is requ...

Type I interferons in anticancer immunity

“…Moreover, treatment with pegylated IFNα after imatinib discontinuation causes sustained remission in a majority of patients with CML 62,63 . This effect has been speculatively attributed to a thera peutic synergy between imatinib and IFNα at the level of malignant cells (because imatinib promotes IFNAR1 expression) 64 , to the IFNαmediated mobilization of Retinoic acid-inducible gene I (RIG-I). A cytosolic sensor that responds to viral double-stranded RNA in the cytosol by inducing type I interferon production.…”

Ubiquitination-mediated regulation of interferon responses

“…Intriguingly, a number of physiological and/or pathological regulators can trigger phosphorylation-induced IFNAR1 ubiquitination and degradation even in the absence of IFN, thereby desensitizing cells to future encounters with ligand. Notably, signaling through the Bcr-Abl oncogene (4), vascular endothelial growth factor (89), additional inflammatory cytokines (30), or ER stress pathway (48) can all have a negative impact IFN signaling by promoting ubiquitination-dependent receptor internalization.…”

Ubiquitin-dependent Turnover of Adenosine Deaminase Acting on RNA 1 (ADAR1) Is Required for Efficient Antiviral Activity of Type I Interferon

“…Therefore, some intracellular mechanisms have evolved to limit excessive activated IFN-I signaling. For example, suppressor of cytokine signaling proteins 1 (SOCS1) inhibits cytokineinduced activation of the JAK family (12), protein kinase D2 (PKD2) promotes IFNAR1 ubiquitination and degradation to limit IFN-I signaling (13)(14)(15), and some of ISG-encoded proteins inhibit the recruitment of JAK to IFN-I receptors (16). Recently, adenosine deaminase acting on RNA 1 (ADAR1) has attracted much attention because of its important negative regulatory effect on IFN-I production and subsequent IFN-I-activated pathways (9,(17)(18)(19).…”