PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced by MOZ-TIF2

Abstract

Leukemias and other cancers possess self-renewing stem cells that help to maintain the cancer1,2. Cancer stem cell eradication is thought to be critical for successful anti-cancer therapy. Using an acute myeloid leukemia (AML) model induced by introducing the leukemia-associated monocytic leukemia zinc finger (MOZ)-TIF2 fusion protein, we show here that AML can be cured by the ablation of leukemia stem cells. The MOZ-fusion proteins interacted with PU.1 to stimulate the expression of macrophage-colony stimulating factor receptor (M-CSFR, also called CSF1R/c-FMS/CD115). Analysis using PU.1-deficient mice demonstrated that PU.1 was essential for MOZ-TIF2 to establish and maintain AML stem cells. Cells expressing high levels of CSF1R (CSF1Rhigh cells), but not those expressing low levels of CSF1R (CSF1Rlow/− cells), showed potent leukemia-initiating activity. Using transgenic mice expressing a drug-inducible suicide gene controlled by the CSF1R promoter, AML was cured by ablation of the CSF1Rhigh cells. Induction of AML was suppressed in CSF1R-deficient mice. CSF1R inhibitors slowed the progress of MOZ-TIF2–induced leukemia. Thus, CSF1Rhigh cells contain leukemia stem cells, and the PU.1-mediated upregulation of CSF1R may be a useful therapeutic target for MOZ leukemia.

TIM-3 as a novel therapeutic target for eradicating acute myelogenous leukemia stem cells

“…In fact, prolonged cytopenia has been observed in AML patients treated with gemtuzumab [45], a recombinant humanized anti-CD33 monoclonal antibody conjugated with the cytotoxic antibiotic calicheamicin. In contrast, CLL-1 [46], CSF1R [47], CD96 [48] and CD99 [16] are all specifically expressed in LSCs. CLL-1 is a transmembrane glycoprotein [49].…”

Stem cell maintenance and disease progression in chronic myeloid leukemia

“…It is thus reasonable and appealing to speculate that targeting a population that can maintain cancer growth may provide clues to effective treatment strategies and, ultimately, a cure to many hematologic malignancies and cancers. Indeed, in the mouse model of MOZ-TIF2-induced AML, forced cell death of the leukemia stem cell population leads to eradication of the disease in vivo [8]. In this Perspective, I will discuss emerging issues and the roles of novel players in stem cell maintenance and disease progression in cancer with a specific focus on chronic myeloid leukemia.…”

miR-146ais a significant brake on autoimmunity, myeloproliferation, and cancer in mice

“…MOZ (monocytic leukemia zinc finger)-TIF2 fusion protein, a high level of CSF1R expression was shown to confer leukemia-initiating activity to myeloid cells (Aikawa et al, 2010). Despite the fact that miR-146a was predicted to target the CSF1R gene by multiple miRNA target prediction algorithms, we failed to detect direct interaction between miR-146a and the 3 UTR of the CSF1R gene, suggesting that upregulation of CSF1R expression on macrophage precursors in miR-146a-null mice may be mediated by an intermediate factor.…”