RESUMEN
MECOM rearrangement (MECOM-R) resulting from 3q26.2 aberrations is often associated with myeloid neoplasms and inferior prognosis in affected patients. Uncommonly, certain 3q26.2/MECOM-R can be subtle/cryptic and consequently overlooked by karyotyping. We identified 17 acute myeloid leukemia (AML) patients (male/female: 13/4 with a median age of 67 years, range 42 to 85 years) with a pericentric inv(3) leading to MECOM-R, with breakpoints at 3p23 (n = 11), 3p25 (n = 3), 3p21 (n = 2) and 3p13 (n = 1) on 3p and 3q26.2 on 3q. These pericentric inv(3)s were overlooked by karyotyping initially in 16 of 17 cases and later detected by metaphase FISH analysis. Similar to the patients with classic/paracentric inv(3)(q21q26.2), patients with pericentric inv(3) exhibited frequent cytopenia, morphological dysplasia (especially megakaryocytes), -7/del(7q), frequent NRAS (n = 6), RUNX1 (n = 5) and FLT-3 (n = 4) mutations and dismal outcomes (median overall survival: 14 months). However, patients with pericentric inv(3) more frequently had AML with thrombocytopenia (n = 15, 88%), relative monocytosis in peripheral blood (n = 15, 88%), decreased megakaryocytes (n = 11, 65%), and lower SF3B1 mutation. We conclude that AML with pericentric inv(3) shares some similarities with AML associated with classic/paracentric inv(3)/GATA2::MECOM but also shows certain unique features. Pericentric inv(3)s are often subtle/cryptic by chromosomal analysis. A reflex FISH analysis for MECOM-R is recommended in myeloid neoplasms showing -7/del(7q).
RESUMEN
OBJECTIVE: Megakaryo/thrombopoiesis is a complex process regulated by multiple signals provided by the bone marrow microenvironment. Because macrophages are relevant components of the bone marrow stroma and their activation induces an upregulation of molecules that can regulate hematopoiesis, we analyzed the impact of these cells on the control of megakaryocyte development and platelet biogenesis. MATERIALS AND METHODS: The different stages of megakaryo/thrombopoiesis were analyzed by flow cytometry using an in vitro model of human cord blood CD34(+) cells stimulated with thrombopoietin in either a transwell system or conditioned media from monocyte-derived macrophages isolated from peripheral blood. Cytokines secreted from macrophages were characterized by protein array and enzyme-linked immunosorbent assay. RESULTS: Resting macrophages released soluble factors that promoted megakaryocyte growth, cell ploidy, a size increase, proplatelet production, and platelet release. Lipopolysaccharide stimulation triggered the secretion of cytokines that exerted opposite effects together with a dramatic switch of CD34(+) commitment to the megakaryocytic lineage toward the myeloid lineage. Neutralization of interleukin-8 released by stimulated macrophages partially reversed the inhibition of megakaryocyte growth. Activation of nuclear factor κB had a major role in the synthesis of molecules involved in the megakaryocyte inhibition mediated by lipopolysaccharide-stimulated macrophages. CONCLUSIONS: Our study extends our understanding about the role of the bone marrow microenvironment in the regulation of megakaryo/thrombopoiesis by showing that soluble factors derived from macrophages positively or negatively control megakaryocyte growth, differentiation, maturation, and their ability to produce platelets.