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

Skorski, Tomasz; Bellacosa, Alfonso; Nieborowska‐Skorska, Margaret; Majewski, Miroslaw; Martinez, Robert; Choi, John K.; Trotta, Rossana; Wlodarski, Pawel; Perrotti, Danilo; Chan, Tung O.; Wasik, Mariusz A.; Tsichlis, Philip N.; Calabretta, Bruno

doi:10.1093/emboj/16.20.6151

Cited by 567Chronic Myeloid Leukemia TreatmentsPI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase Signaling

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

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Skorski, Tomasz, Bellacosa, Alfonso, Nieborowska‐Skorska, Margaret, Majewski, Miroslaw, Martinez, Robert, Choi, John K., Trotta, Rossana, Wlodarski, Pawel +5 more·1997·The EMBO Journal

DOI 10.1093/emboj/16.20.6151PMC PMC1326299

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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.

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Previous reports indicated survival signals positively regulate Mdm2 and lead to stabilization of the protein.
“Previous reports have indicated that survival signals positively regulate Mdm2 and lead to stabilization of the protein (54 -57).”
From Stabilization of Mdm2 via Decreased Ubiquitination Is Mediated by Protein Kinase B/Akt-dependent Phosphorylation (2004) · cites this paper as [54]

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Ahmed,N.N., Grimes,H.L., Bellacosa,A., Chan,T.O. and Tsichlis,P.N. (1997) Transduction of IL-2 anti-apoptotic and proliferative signals via Akt. Proc. Natl Acad. Sci. USA, 94, 3627-3632.

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Oncogenic kinase signalling.
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Molecular signature of CD34+ hematopoietic stem and progenitor cells of patients with CML in chronic phase
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LY294002 inhibits LPS-induced NO production through a inhibition of NF-κB activation: independent mechanism of phosphatidylinositol 3-kinase
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The phosphatidylinositol 3‐kinase inhibitor LY294002 potently blocks Kv currents via a direct mechanism
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D010 Mesenchymal stem cells protect cardiomyocytes from reperfusion injury through a paracrine activation of the PI3 kinase pathway
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(643)
Sun, R., Yan, J., & Willis, W. D. (2006) · Journal of Pain · doi:10.1016/j.jpain.2006.01.045

Authors: Skorski, T., Bellacosa, A., Nieborowska‐Skorska, M., Majewski, M., Martinez, R., Choi, J. K., Trotta, R., Wlodarski, P., Perrotti, D., Chan, T. O., Wasik, M. A., Tsichlis, P. N., & Calabretta, B.
Affiliations: Fox Chase Cancer Center (US)
Thomas Jefferson University (US)
University of Pennsylvania (US)
Corresponding author: Calabretta, Bruno
ORCID: Wlodarski, Pawel
Venue: The EMBO Journal
Publisher: Springer Science and Business Media LLC
Published: 1997-10-15
Volume: 16
Issue: 20
Pages: 6151-6161
ISSN: 0261-4189 (ISSN-L)
1460-2075
DOI: 10.1093/emboj/16.20.6151
PMC: PMC1326299
OpenAlex: W2116396726
Cited by: 567
References: 78
Citations by year: 2026: 3 · 2025: 2 · 2024: 2 · 2023: 4 · 2022: 8 · 2021: 3 · 2020: 3 · 2019: 5 · 2018: 12 · 2017: 9 · 2016: 11 · 2015: 15 · 2014: 19 · 2013: 16 · 2012: 18
FWCI: 13.64
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: The EMBO Journal (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
Funders: National Institutes of Health (7r29ca070815-04)
National Cancer Institute (1R29 CA70815)
Topics: Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: BCR-ABL, PI-3K/Akt pathway, phosphatidylinositol 3-kinase, Akt kinase, SH2 domain, p85 regulatory subunit, hematopoietic cell transformation, leukemogenesis, wortmannin, p21ras, p70 S6 kinase, c-Myc, Bcl-2, SCID mice
MeSH terms: Animals, Bone Marrow, Bone Marrow Cells, Cell Transformation, Neoplastic, Enzyme Activation, Leukemia, Experimental, Liver, Mice, Inbred C57BL, Proto-Oncogene Proteins, Spleen, Signal Transduction, Fusion Proteins, bcr-abl, Genes, myc, Mice, SCID, Protein Serine-Threonine Kinases, Genes, bcl-2, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Mice

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

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