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.
|Data di pubblicazione:||1997|
|Titolo:||Transformation of hematopoietic cells by BCR/ABL requires activation of PI-3k/Akt dependent pathway.|
|Autore/i:||Skorski T; Bellacosa A; Nieborowska-Skorska M; Majewski M; Martinez R; Choi JK; Trotta R; Wlodarski P; Perrotti D; Chan TO; Wasik MA; Tsichlis PN; Calabretta B.|
|Codice identificativo Scopus:||2-s2.0-0030710188|
|Citazione:||Transformation of hematopoietic cells by BCR/ABL requires activation of PI-3k/Akt dependent pathway / Skorski T; Bellacosa A; Nieborowska-Skorska M; Majewski M; Martinez R; Choi JK; Trotta R; Wlodarski P; Perrotti D; Chan TO; Wasik MA; Tsichlis PN; Calabretta B.. - In: EMBO JOURNAL. - ISSN 0261-4189. - ELETTRONICO. - 16(1997), pp. 6151-6161.|
|Tipologia||Articolo su rivista|
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