Altered transcription of the stem cell leukemia gene in myelofibrosis with myeloid metaplasia

Abstract

An increased number of circulating CD34 þ hematopoietic progenitors with a prominent proliferation of the megakaryocytic (MK) population are the hallmarks of the myeloproliferation in myelofibrosis with myeloid metaplasia (MMM). Analyzing the potential contribution of the stem cell leukemia (SCL) gene in MMM myeloproliferation was doubly interesting for SCL is expressed both in primitive-uncommitted progenitor cells and erythroid/MK cells, its transcription differentially initiating from promoter 1b and 1a, respectively. Our results show that: (i) the expression of SCL transcript is increased in peripheral blood mononuclear cells (PBMCs) from patients; (ii) SCL gene transcription is altered in MMM CD34 þ progenitor cells sorted into CD34 þ CD41 þ and CD34 þ CD41 À subpopulations. Actually, in patients, SCL transcription initiated at promoter 1b is restricted to primitive CD34 þ CD41 À progenitor cells, while it is detectable in both cell subsets from healthy subjects; (iii) the full-length isoform of SCL protein is present in patients' CD34 þ cells and in PBMC; in the latter the SCL-expressing cells mainly belong to the MK lineage in which its sublocalization is both nuclear and cytoplasmic, which contrasts with the sole nuclear staining observed in normal MK cells. Our demonstration of altered expression and transcription of SCL in patients' hematopoietic cells emphasizes the possible contribution of this regulatory nuclear factor to the hematopoietic dysregulation, which is a feature of myelofibrosis with myeloid metaplasia.

New insights into the pathogenesis and drug treatment of myelofibrosis

“…Another study, however, did not reveal abnormal promoter methylation involving several other tumor-suppressor genes including p14, p15(INK4B), p16(INK4A), and Rb [24]. Other molecules with altered expression in MMM include high-mobility group protein A2 (HMGPA2) and stem cell leukemia gene, both of which were shown to be overexpressed in blood mononuclear cells [25,26]. Whether such preliminary observations will lead to therapeutically relevant discoveries in MMM remains to be seen.…”

IL-8 and its CXCR1 and CXCR2 receptors participate in the control of megakaryocytic proliferation, differentiation, and ploidy in myeloid metaplasia with myelofibrosis

“…11,12 While the underlying molecular genetic alterations remain unknown, recent data led us to propose a model integrating alterations in the expression and function of MK nuclear regulatory factors and in the complex network of humoral and cellular interactions between hematopoietic cells and stroma in the pathogenetic mechanisms of the disease. 13,14 Interleukin 8 (IL-8) is a member of the family of chemokines related by a CXC motif. It binds to two 7-transmembrane-domain CXC chemokine receptor 1 (CXCR1) and 2 (CXCR2) receptors that belong to the superfamilly of G protein-coupled receptors with high affinity.…”

Immunoproteasome Genes Are Modulated in CD34+ JAK2V617F Mutated Cells from Primary Myelofibrosis Patients

“…The impairment of the immunologic framework has emerged almost always, showing an alteration of the pro-inflammatory, pro-differentiation and anti-apoptotic transcription lines. As an example, in idiopathic myelofibrosis (IM) [53], and in PMF [54][55][56] it emerged from the analyses that the WT1 gene is highly modulated. A T-cell receptor (TCR) that specifically reacts with WT1 peptide in the context of HLA-A * 24:02 has been identified [57].…”