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


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).


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.
Richter
Karin
K
Umeå Center for Molecular Medicine, Umeå University, 901 87 Umeå, Sweden.
Pinto do O
Perpétua
P
Hägglund
Anna-Carin
AC
Wahlin
Anders
A
Carlsson
Leif
L
D000740:Anemia / Q000235:genetics; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002908:Chronic Disease; D003114:Colony-Forming Units Assay; D018450:Disease Progression; D004906:Erythrocyte Count; D004909:Erythrocyte Indices; D015973:Gene Expression Regulation, Leukemic; D005914:Globins / Q000096:biosynthesis* / Q000235:genetics; D005956:Glucose-6-Phosphate Isomerase / Q000235:genetics; D006411:Hematopoiesis, Extramedullary / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D060850:LIM-Homeodomain Proteins; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology; D007951:Leukemia, Myeloid / Q000235:genetics / Q000473:pathology; D007958:Leukocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000473:pathology; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011533:Proviruses / Q000235:genetics; D011828:Radiation Chimera; D013154:Spleen / Q000473:pathology; D013163:Splenomegaly / Q000209:etiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic
D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; C489784:Lhx2 protein, mouse; D014157:Transcription Factors; D005914:Globins; D019009:Proto-Oncogene Proteins c-kit; D005956:Glucose-6-Phosphate Isomerase