Crucial factors of the inflammatory microenvironment (IL-1β/TNF-α/TIMP-1) promote the maintenance of the malignant hemopoietic clone of myelofibrosis: an in vitro study.
Along with molecular abnormalities (mutations in JAK2, Calreticulin (CALR) and MPL genes), chronic inflammation is the major hallmark of Myelofibrosis (MF). Here, we investigated the in vitro effects of crucial factors of the inflammatory microenvironment (Interleukin (IL)-1β, Tumor Necrosis Factor (TNF)-α, Tissue Inhibitor of Metalloproteinases (TIMP)-1 and ATP) on the functional behaviour of MF-derived circulating CD34+ cells.We found that, regardless mutation status, IL-1β or TNF-α increases the survival of MF-derived CD34+ cells. In addition, along with stimulation of cell cycle progression to the S-phase, IL-1β or TNF-α ± TIMP-1 significantly stimulate(s) the in vitro clonogenic ability of CD34+ cells from JAK2V617 mutated patients. Whereas in the JAK2V617F mutated group, the addition of IL-1β or TNF-α + TIMP-1 decreased the erythroid compartment of the CALR mutated patients. Megakaryocyte progenitors were stimulated by IL-1β (JAK2V617F mutated patients only) and inhibited by TNF-α. IL-1β + TNF-α + C-X-C motif chemokine 12 (CXCL12) ± TIMP-1 highly stimulates the in vitro migration of MF-derived CD34+ cells. Interestingly, after migration toward IL-1β + TNF-α + CXCL12 ± TIMP-1, CD34+ cells from JAK2V617F mutated patients show increased clonogenic ability.Here we demonstrate that the interplay of these inflammatory factors promotes and selects the circulating MF-derived CD34+ cells with higher proliferative activity, clonogenic potential and migration ability. Targeting these micro-environmental interactions may be a clinically relevant approach.
Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.
Daria
D
Sollazzo
Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.
Dorian
D
Forte
Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.
Nicola
N
Polverelli
Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.
Marco
M
Romano
Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.
Margherita
M
Perricone
Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.
Lara
L
Rossi
Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.
Emanuela
E
Ottaviani
Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.
Simona
S
Luatti
Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.
Giovanni
G
Martinelli
Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.
Nicola
N
Vianelli
Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.
Michele
M
Cavo
Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.
Francesca
F
Palandri
Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.
Lucia
L
Catani
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000097:blood / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D055728:Primary Myelofibrosis / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000494:pharmacology*
D018952:Antigens, CD34; D053583:Interleukin-1beta; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha
circulating CD34+ cells; inflammatory microenvironment; migration; myelofibrosis; survival