Inactivation of PU.1 in adult mice leads to the development of myeloid leukemia

Abstract

Genetically primed adult C57BL mice were deleted of exon 5 of the gene encoding the transcription factor PU.1 by IFN activation of Cre recombinase. After a 13-week delay, conditionally deleted (PU.1 ؊/؊ ) mice began dying of myeloid leukemia, and 95% of the mice surviving from early postinduction death developed transplantable myeloid leukemia whose cells were deleted of PU.1 and uniformly Gr-1 positive. The leukemic cells formed autonomous colonies in semisolid culture with varying clonal efficiency, but colony formation was enhanced by IL-3 and sometimes by granulocyte-macrophage colony-stimulating factor. Nine of 13 tumors analyzed had developed a capacity for autocrine IL-3 or granulocyte-macrophage colony-stimulating factor production, and there was evidence of rearrangement of the IL-3 gene. Acquisition of autocrine growth-factor production and autonomous growth appeared to be major events in the transformation of conditionally deleted PU.1 ؊/؊ cells to fully developed myeloid leukemic populations.mouse ͉ transplantation ͉ growth-factor production

Reduction in PU.1 activity results in a block to B-cell development, abnormal myeloid proliferation, and neonatal lethality

“…Interestingly, reduced levels of PU.1 promote hyperproliferation of immature myeloid precursor cells during neonatal but not fetal development. Another study also concluded that inactivation of PU.1 in adult hematopoiesis led to increased proliferation of immature myeloid cells, and eventually acute myeloid leukemia [24,25]. An important future area of investigation will be to determine why low levels of PU.1 activity result in a hyperproliferation of immature myeloid cells in vivo.…”

Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder

“…Of note, the reduced expression or altered function of some of these targets has been linked to AML, as in the case of PU.1 and Picalm ( 24,25 ), or myeloproliferative conditions, as is true for Cutl1 and Csf1r ( 26,27 ). Other identifi ed targets have been implicated in control of various aspects of hematopoiesis involving many of the cell types that are perturbed in mice expressing miR-155 in HSCs.…”

Transcriptional dysregulation during myeloid transformation in AML

“…In addition, deletion of one PU.1 gene copy combined with suppression of the other copy by PML-RARA was reported as the mechanism in mouse APL (Walter et al, 2005). Whereas these observations indicate that low but detectable amounts of PU.1 might favor the malignant potential of leukemic cells, this view was challenged by a recent report suggesting that complete loss of PU.1 can (also) lead to AML, at least in mice (Metcalf et al, 2006).…”