Stat5 is indispensable for the maintenance of bcr/abl ‐positive leukaemia

Abstract

Tumourigenesis caused by the Bcr/Abl oncoprotein is a multi-step process proceeding from initial to tumour-maintaining events and finally results in a complex tumour-supporting network. A key to successful cancer therapy is the identification of critical functional nodes in an oncogenic network required for disease maintenance. So far, the transcription factors Stat3 and Stat5a/b have been implicated in bcr/abl-induced initial transformation. However, to qualify as a potential drug target, a signalling pathway must be required for the maintenance of the leukaemic state. Data on the roles of Stat3 or Stat5a/b in leukaemia maintenance are elusive. Here, we show that both, Stat3 and Stat5 are necessary for initial transformation. However, Stat5-but not Stat3-deletion induces G0/G1 cell cycle arrest and apoptosis of imatinib-sensitive and imatinib-resistant stable leukaemic cells in vitro. Accordingly, Stat5-abrogation led to effective elimination of myeloid and lymphoid leukaemia maintenance in vivo. Hence, we identified Stat5 as a vulnerable point in the oncogenic network downstream of Bcr/Abl representing a case of non-oncogene addiction (NOA).

Ebf1orPax5haploinsufficiency synergizes with STAT5 activation to initiate acute lymphoblastic leukemia

“…In contrast, we previously demonstrated that mice expressing a constitutively active form of STAT5 develop ALL, albeit with low penetrance (Burchill et al, 2003;Nakayama et al, 2009). More recent data using complete STAT5-null mice has demonstrated that STAT5 is required for transformation by Bcr-Abl-expressing retroviruses (Hoelbl et al, 2006(Hoelbl et al, , 2010. Supporting these previous findings in mouse models of leukemia, our data examining 129 patients with ALL confirm that STAT5 activation occurs in a substantial fraction of ALL cases.…”

Inhibition of activated STAT5 in Bcr/Abl expressing leukemia cells with new pimozide derivatives

“…5 Differently from normal cells in which STAT5 is activated by JAK2, in ALL and CML the products of the fusion proteins TEL/ JAK2 and BCR/ABL activate directly STAT5 proteins. Activated STAT5 seems to plays a crucial role in growth and survival of CLM cells suggesting that drugs able to target STAT5 could be useful for the treatment of this type of leukemia, especially for CML resistant to imatinib or other BCR/ABL targeted molecules.…”

Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy

“…Among these, AKT and STAT5 are critical downstream signaling molecules constitutively phosphorylated imatinibresistant chronic myeloid leukemia (CML) and KIT D816V + SM. 4,5 This has been demonstrated in vitro using KIT D816V + and BCR-ABL1 + imatinib-resistant cell lines, where inhibition of phosphorylation of these targets has shown their crucial role in cell proliferation. 6,7 It has also been reported that STAT5 and AKT remained activated in neoplastic myeloid cells, even after inhibition of BCR-ABL1 by TKIs.…”