Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway

Abstract

The BCR/ABL oncogenic tyrosine kinase activates phosphatidylinositol 3-kinase (PI-3k) by a mechanism that requires binding of BCR/ABL to p85, the regulatory subunit of PI-3k, and an intact BCR/ABL SH2 domain. SH2 domain BCR/ABL mutants deficient in PI-3k activation failed to stimulate Akt kinase, a recently identified PI-3k downstream effector with oncogenic potential, but did activate p21 RAS and p70 S6 kinase. The PI-3k/Akt pathway is essential for BCR/ABL leukemogenesis as indicated by experiments demonstrating that wortmannin, a PI-3k specific inhibitor at low concentrations, suppressed BCR/ABL-dependent colony formation of murine marrow cells, and that a kinase-deficient Akt mutant with dominant-negative activity inhibited BCR/ABL-dependent transformation of murine bone marrow cells in vitro and suppressed leukemia development in SCID mice. In complementation assays using mouse marrow progenitor cells, the ability of transformation-defective SH2 domain BCR/ABL mutants to induce growth factor-independent colony formation and leukemia in SCID mice was markedly enhanced by expression of constitutively active Akt. In retrovirally infected mouse marrow cells, the BCR/ABL mutant lacking the SH2 domain was unable to upregulate the expression of c-Myc and Bcl-2; in contrast, expression of a constitutively active Akt mutant induced Bcl-2 and c-Myc expression, and stimulated the transcription activation function of c-Myc. Together, these data demonstrate the requirement for the BCR/ABL SH2 domain in PI-3k activation and document the essential role of the PI-3k/Akt pathway in BCR/ABL leukemogenesis.

The oncogenic TEL/PDGFRβ fusion protein induces cell death through JNK/SAPK pathway

“…An example of this scenario is the cellular transformation of haematopoietic cells by the fusion protein BCR-ABL which occurs via PI-3 kinase/AKT signalling pathways (Skorski et al, 1997). Other alternative mechanisms might also exist as our previous studies indicated that the activity of the c-myc protooncogene is essential for the transforming capacity of T/P .…”

“…This e ect seems likely to involve activation of JNK/SAPK cascade since overexpression of a dominant-interfering mutant of c-Jun suppressed BCR/Abl-induced cellular transformation (Raitano et al, 1995). Furthermore, PI-3 kinase has also been implicated in cellular transformation by BCR/ABL (Skorski et al, 1997). If PI-3 kinase lies downstream of T/P to JNK/SAPK, one would expect that PI-3 kinase activity would mirror JNK/SAPK activity.…”

“…Recently, it has been reported that a dominant negative form of PI-3 kinase as well as PI-3 kinase inhibitors block EGF-induced JNK/SAPK activation, although these inhibitors had no e ect on JNK/SAPK activation induced by UV irradiation, osmotic shock, or TNFa (Logan et al, 1997). Furthermore, both PI-3 kinase and JNK/SAPK pathway activation has been shown to be involved in the transforming potential of the human leukaemia oncogene, BCR/ABL (Skorski et al, 1997;Raitano et al, 1995). Because T/P is also associated with haematological malignancies and more precisely with chronic myelomonocytic leukaemia (CMML), we investigated the possible role of JNK/SAPK cascade in transformation of the murine haematopoietic cell line Ba/F3 which requires interleukin-3 (IL-3) for growth and survival.…”

The underestimated role of basophils in Ph+ chronic myeloid leukaemia

“…The resulting oncoprotein, BCR‐ABL1, acts as a cytoplasmic driver exhibiting constitutive tyrosine kinase (TK) activity. BCR‐ABL1 triggers several major downstream signalling molecules, including RAS, phosphoinositide 3‐kinase (PI3K) and signal transducer and activator of transcription 5 (STAT5) 4, 5, 6. These molecules and the related oncogenic machinery are considered to play a major role in the evolution and pathogenesis of CML.…”

“…In the CP of CML, BCR‐ABL1 is a major driver of disease evolution, cell survival and proliferation. By contrast, in AP and BP, additional factors and pro‐oncogenic molecules play a critical role in disease progression and drug resistance 4, 5, 6, 9, 10, 11. A key laboratory feature of patients with advanced CML is marked and sometimes even excessive basophilia 12, 13, 14.…”