Dormant Tumor Cells Develop Cross-Resistance to Apoptosis Induced by CTLs or Imatinib Mesylate via Methylation of Suppressor of Cytokine Signaling 1

Abstract

In the BCR/ABL DA1-3b mouse model of acute myelogenous leukemia, dormant tumor cells may persist in the host in a state of equilibrium with the CD8 + CTL-mediated immune response by actively inhibiting T cells. Dormant tumor cells also show a progressive decrease of suppressor of cytokine signaling 1 (SOCS1) gene expression and a deregulation of the Janus-activated kinase/signal transducers and activators of transcription (JAK/STAT) pathway due to methylation of the SOCS1 gene. Dormant tumor cells were more resistant to apoptosis induced by specific CTLs, but resistance decreased when SOCS1 expression was restored via demethylation or gene transfer. AG490 JAK2 inhibitor decreased the resistance of dormant tumor cells to CTLs, but MG132 proteasome inhibitor was effective only in SOCS1-transfected cells. Thus, SOCS1 regulation of the JAK/STAT pathways contributes to the resistance of tumor cells to CTL-mediated killing. Resistance of dormant tumor cells to apoptosis was also observed when induced by irradiation, cytarabine, or imatinib mesylate, but was reduced by SOCS1 gene transfer. This cross-resistance to apoptosis was induced by interleukin 3 (IL-3) overproduction by dormant tumor cells and was reversed with an anti-IL-3 antibody. Thus, tumor cells that remain dormant for long periods in the host in spite of a specific CTL immune response may deregulate their JAK/STAT pathways and develop crossresistance to various treatments through an IL-3 autocrine loop. These data suggest possible new therapeutic targets to eradicate dormant tumor cells. [Cancer Res 2007;67(9):4491-8]

BCR-ABL mutants spread resistance to non-mutated cells through a paracrine mechanism

“…In the DA1-3b BCR-ABL mouse model of tumor dormancy, dormant leukemic cells that persist for 1 year, in spite of an immune response, develop resistance to apoptosis through an interleukin (IL) 3 autocrine loop. 6 This IL3 loop also led to imatinib resistance, even though these cells had never been exposed to kinase inhibitors, and did not show any BCR-ABL mutations. Thus, cells can become resistant to kinase inhibitors through BCR-ABL-independent mechanisms.…”

Human embryo immune escape mechanisms rediscovered by the tumor

“…A further example of similar gene expression between embryo and tumor is that of SOCS genes, which are cytokine signaling suppressors. In gestational tissue, for example, the expression of these SOCS proteins is reduced (Blumenstein et al, 2002), and Saudemont et al (2007) reported a reduced expression of SOCS1 in a murine model of acute myeloid leukemia, which would seem to render such dorment tumor cells resistant to CTL-induced apoptosis, thus creating a kind of balance between CTL-specific and dormant tumor cells.…”

Enhanced ABL-inhibitor-induced MAPK-activation in T315I-BCR-ABL-expressing cells: a potential mechanism of altered leukemogenicity

“…Other mechanisms include BCR-ABL-amplification, drug influx/efflux mechanisms, or activation of BCR-ABL bypassing signaling pathways (Hochhaus and La Rosée 2004;Lahaye et al 2005). Recent publications provide growing evidence that recruitment of cytokine signaling may precede and govern the development of resistance (Dorsey et al 2002;Burchert et al 2005;Wang et al 2007;Saudemont et al 2007;Williams et al 2007).…”