TAp63 regulates VLA-4 expression and chronic lymphocytic leukemia cell migration to the bone marrow in a CD74-dependent manner.
The hallmark of chronic lymphocytic leukemia (CLL) is the relentless accumulation of mature lymphocytes, mostly due to their decreased apoptosis. CD74 was recently shown to serve as a survival receptor on CLL cells. In this study, we show that stimulation of CD74 with its natural ligand, migration inhibitory factor, initiates a signaling cascade that results in upregulation of TAp63, which directly regulates CLL survival. In addition, TAp63 expression elevates the expression of the integrin VLA-4, particularly during the advanced stage of the disease. Blocking of CD74, TAp63, or VLA-4 inhibits the in vivo homing of CLL cells to the bone marrow (BM). Thus, CD74 and its target genes TAp63 and VLA-4 facilitate migration of CLL cells back to the BM, where they interact with the supportive BM environment that rescues them from apoptosis. These results could form the basis of novel therapeutic strategies aimed at blocking homing of CLL cells in their return to the BM and attenuating their survival.
Binsky
Inbal
I
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Lantner
Frida
F
Grabovsky
Valentin
V
Harpaz
Nurit
N
Shvidel
Lev
L
Berrebi
Alain
A
Goldenberg
David M
DM
Leng
Lin
L
Bucala
Richard
R
Alon
Ronen
R
Haran
Michal
M
Shachar
Idit
I
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D001854:Bone Marrow Cells / Q000276:immunology* / Q000473:pathology*; D002464:Cell Migration Inhibition / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D039041:Integrin alpha4beta1 / Q000096:biosynthesis / Q000235:genetics*; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000502:physiology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D015398:Signal Transduction / Q000276:immunology; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology
D019138:Antibodies, Blocking; D000944:Antigens, Differentiation, B-Lymphocyte; D000951:Antigens, Neoplasm; D051017:Apoptosis Regulatory Proteins; D000949:Histocompatibility Antigens Class II; D039041:Integrin alpha4beta1; D008263:Macrophage Migration-Inhibitory Factors; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C045084:invariant chain; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human