Constitutive activation of STAT5 and Bcl-xL overexpression can induce endogenous erythroid colony formation in human primary cells

Abstract

The biologic hallmark of polycythemia vera (PV) is the formation of endogenous erythroid colonies (EECs) with an erythropoietin-independent differentiation. Recently, it has been shown that an activating mutation of JAK2 (V617F) was at the origin of PV. In this work, we studied whether the STAT5/Bcl-xL pathway could be responsible for EEC formation. A constitutively active form of STAT5 was transduced into human erythroid progenitors and induced an erythropoietin-independent terminal differentiation and EEC formation. Furthermore, Bcl-xL overexpression in erythroid progenitors was also able to induce erythroid colonies despite the absence of erythropoietin. Conversely, siRNAmediated STAT5 and Bcl-xL knock-down in human erythroid progenitors inhibited colony-forming unit-erythroid (CFU-E) formation in the presence of Epo. Altogether, these results demonstrate that a sustained level of the sole Bcl-xL is capable of giving rise to Epo-independent erythroid colony formation and suggest that, in PV patients, JAK2 V617F may induce EEC via the STAT5/Bcl-xL pathway.

SOCS-mediated downregulation of mutant Jak2 (V617F, T875N and K539L) counteracts cytokine-independent signaling

“…In PV, activation of signal transducer and activator of transcription (STAT) 5 and STAT3 was described (Roder et al, 2001;Garcon et al, 2006). The constitutively active Jak2 mutants have been shown to lead to cytokine receptor-dependent constitutive activation of various signaling proteins, such as STATs, mitogen-activated protein kinases and phosphatidylinositol-3-kinase/AKT (James et al, 2005;Lu et al, 2005;Mercher et al, 2006;Scott et al, 2007).…”

The role of Janus Kinase 2 V617F mutation in extramedullary hematopoiesis of the spleen in neoplastic myeloid disorders

“…Targeted genes, including the antiapoptotic protein Bcl-xL, have been implicated in vital cellular processes such as proliferation and survival. [13][14][15][16][17] Furthermore, retroviral transduction of JAK2 V617F into murine hematopoietic stem cells was recently shown to result in the development of a polycythemia-like phenotype. 7,18 The role of JAK2 V617F in splenic EMH has not been previously studied.…”

Miscreant myeloproliferative disorder stem cells

“…More recent research suggests that expression of JAK2V617F induces expression of an antiapoptotic protein, Bcl-xL, thereby blocking apoptosis and enhancing survival of JAK2V617F-expressing cells. 98 A recent report suggested that human telomerase reverse transcriptase (hTERT) known to be involved in regulating telomere length, genomic stability and cell survival may also play a role in EPO-induced red blood cell production. 99 EPO was shown to activate hTERT gene expression through a JAK2/STAT5/c-myc axis.…”