Selective regulation of Bcl-XL by a Jak kinase-dependent pathway is bypassed in murine hematopoietic malignancies.
Bcl-2 family proteins are key regulators of apoptosis and function as cell death antagonists (e.g., Bcl-2, Bcl-XL, and Mcl-1) or agonists (e.g., Bax, Bad, and Bak). Here we report that among the Bcl-2 family of proteins tested (Bcl-2, Bcl-XL, Mcl-1, Bax, Bad, and Bak), Bcl-XL was unique in that its protein levels were tightly regulated by hemopoietins in both immortal and primary myeloid progenitors. Investigating signaling pathways utilized by cytokine receptors established that the regulation of Bcl-XL protein levels is mediated by the Jak kinase pathway and is independent of other signaling effectors including STATs, PI-3' kinase, and Ras. Moreover, we provide the first direct evidence that Bcl-X is altered in cancer, because bcl-X expression was activated selectively by retroviral insertions in murine myeloid and T-cell hemopoietic malignancies. Tumors harboring bcl-X insertions had altered bcl-X RNAs, expressed elevated levels of Bcl-XL protein, and lacked the requirements for cytokines normally essential for cell survival. Finally, overexpression of Bcl-XL effectively protected IL-3-dependent myeloid cells from apoptosis following removal of trophic factors. Therefore, Bcl-XL functions as a key cytokine regulated anti-apoptotic protein in myelopoiesis and contributes to leukemia cell survival.
Packham
G
G
Ludwig Institute for Cancer Research, Imperial College School of Medicine at St. Mary's, London W2 1PG, UK.
White
E L
EL
Eischen
C M
CM
Yang
H
H
Parganas
E
E
Ihle
J N
JN
Grillot
D A
DA
Zambetti
G P
GP
Nuñez
G
G
Cleveland
J L
JL
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic; D016298:Hematopoietic Cell Growth Factors / Q000502:physiology*; D053614:Janus Kinase 2; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism*; D015458:Leukemia, T-Cell / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D016415:Sequence Alignment; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D016298:Hematopoietic Cell Growth Factors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2