Gfi-1 inhibits proliferation and colony formation of p210BCR/ABL-expressing cells via transcriptional repression of STAT 5 and Mcl-1

Abstract

Expression of the transcription repressor Gfi-1 is required for the maintenance of murine hematopoietic stem cells. In human cells, ectopic expression of Gfi-1 inhibits and RNA interference-mediated Gfi-1 downregulation enhances proliferation and colony formation of p210BCR/ABL expressing cells. To investigate the molecular mechanisms that may explain the effects of perturbing Gfi-1 expression in human cells, Gfi-1-regulated genes were identified by microarray analysis in K562 cells expressing the tamoxifen-regulated Gfi-1-ER protein.STAT 5B and Mcl-1, two genes important for the proliferation and survival of hematopoietic stem cells, were identified as direct and functionally relevant Gfi-1 targets in p210BCR/ABL-transformed cells because: (i) their expression and promoter activity was repressed by Gfi-1 and (ii) when constitutively expressed blocked the proliferation and colony formation inhibitory effects of Gfi-1. Consistent with these findings, genetic or pharmacological inhibition of STAT 5 and/or Mcl-1 markedly suppressed proliferation and colony formation of K562 and CD34 þ chronic myelogenous leukemia (CML) cells. Together, these studies suggest that the Gfi-1STAT 5B/Mcl-1 regulatory pathway identified here can be modulated to suppress the proliferation and survival of p210BCR/ABL-transformed cells including CD34 þ CML cells.

Sustained inhibition of STAT5, but not JAK2, is essential for TKI-induced cell death in chronic myeloid leukemia

“…STAT5 is a critical participant in TKI resistance 11,12 and the clinically available dopamine reuptake inhibitor pimozide has been demonstrated to inhibit STAT5 activation in CML cells, subsequently enhancing TKI-induced apoptosis. 3,15 We establish that treatment with STAT5i, which targets the SH2 domain of STAT5, 36 had little effect as a sole agent in cell lines or primary CP-CML CD34 þ cells. Inhibition of STAT5 with pimozide or STAT5i in combination with only 30 min exposure to TKI, induced death in both BCR-ABL1 þ cell lines and primitive CP-CML CD34 þ cells despite complete removal of dasatinib or imatinib after.…”

“…1 The signal transducer and activator of transcription 5 (STAT5) is constitutively active in CML cells as a result of Bcr-Abl activation. 2 In addition, the STAT5 transcriptional repressor Gfi-1 is down regulated in CML, 3 and we have previously demonstrated that low levels of GFI-1 at diagnosis predict progression to blast crisis. 4 Conventionally, STAT5 activation occurs in response to cytokine signaling through JAK kinases.…”

A novel compound against oncogenic Aurora kinase A overcomes imatinib resistance in chronic myeloid leukemia cells

“…BCR-ABL is a tyrosine kinase responsible for malignant transformation by activating multiple signal pathways, including the PI3K/Akt, MAPK/ERK and STATs (2)(3)(4), leading to aberrant cell survival (5,6). The successful introduction of the tyrosine kinase inhibitors (TKIs), constitutes an effective strategy in CML.…”

Which TKI? An embarrassment of riches for chronic myeloid leukemia patients

“…35 That study, along with their previous work, 36 demonstrated the biological importance of the GFI1/STAT5B/Mcl-1 regulatory pathway on proliferation and survival of CML cells. In a study of CP-CML patients, Kok et al demonstrated that decreased GFI1 expression at diagnosis is highly correlative with disease progression and transformation to BC.…”