Lhx2 expression in hematopoietic progenitor/stem cells in vivo causes a chronic myeloproliferative disorder and altered globin expression

Abstract

BACKGROUND AND OBJECTIVES: Chronic myeloproliferative disorders (CMDs) are thought to be due to mutation(s) in a single clone at the level of the hematopoietic stem cell (HSC). Such mutations and additional mutations causing progression of the disease are largely unknown. Chronic myeloid leukemia (CML) is a CMD characterized by a chromosomal translocation between chromosomes 9 and 22 creating the fusion protein BCR-ABL. This translocation has also been suggested to cause mis-expression of the LIM-homeobox gene Lhx2 in hematopoietic cells. We have previously shown that Lhx2 expression in mouse HSC generates cytokine-dependent stem cell-like cell lines that can produce long-term repopulation in stem cell-deficient mice. DESIGN AND METHODS: Since the consequences of Lhx2 expression in hematopoietic cells in vivo were unknown, mice engrafted with the stem cell-like cell lines were analyzed in detail for any pathologic changes. RESULTS: Expression of Lhx2 was maintained in vivo and most engrafted mice developed a myeloproliferative disorder characterized by splenomegaly, extramedullary hematopoiesis and anemia. The disorder was transplantable and the Lhx2-expressing cells could also cause acute leukemia. The anemia was due to both a reduced number of circulating erythrocytes and a reduced mean corpuscular hemoglobin concentration (MCHC). INTERPRETATION AND CONCLUSIONS: These observations suggest that constitutive expression of Lhx2 in hematopoietic cells causes CMD, and also that a novel cell-autonomous mechanism can contribute to anemia.