TY - JOUR
T1 - Molecular basis of clonal expansion of hematopoiesis in 2 patients with paroxysmal nocturnal hemoglobinuria (PNH)
AU - Inoue, Norimitsu
AU - Izui-Sarumaru, Tomohisa
AU - Murakami, Yoshiko
AU - Endo, Yuichi
AU - Nishimura, Jun Ichi
AU - Kurokawa, Ken
AU - Kuwayama, Maki
AU - Shime, Hiroaki
AU - Machii, Takashi
AU - Kanakura, Yuzuru
AU - Meyers, Gabrielle
AU - Wittwer, Carl
AU - Chen, Zhong
AU - Babcock, William
AU - Frei-Lahr, Debra
AU - Parker, Charles J.
AU - Kinoshita, Taroh
PY - 2006/12/15
Y1 - 2006/12/15
N2 - Somatic mutation of PIGA in hematopoietic stem cells causes deficiency of glycosyl phosphatidylinositol-anchored proteins in paroxysmal nocturnal hemoglobinuria (PNH) that underlies the intravascular hemolysis but does not account for expansion of the PNH clone. Immune mechanisms may mediate clonal selection but appear insufficient to account for the clonal dominance necessary for PNH to become clinically apparent. Herein, we report 2 patients with PNH whose PIGA-mutant cells had a concurrent, acquired rearrangement of chromosome 12. In both cases, der(12) had a break within the 3′ untranslated region of HMGA2, the architectural transcription factor gene deregulated in many benign mesenchymal tumors, that caused ectopic expression of HMGA2 in the bone marrow. These observations suggest that aberrant HMGA2 expression, in concert with mutant PIGA, accounts for clonal hematopoiesis in these 2 patients and suggest the concept of PNH as a benign tumor of the bone marrow.
AB - Somatic mutation of PIGA in hematopoietic stem cells causes deficiency of glycosyl phosphatidylinositol-anchored proteins in paroxysmal nocturnal hemoglobinuria (PNH) that underlies the intravascular hemolysis but does not account for expansion of the PNH clone. Immune mechanisms may mediate clonal selection but appear insufficient to account for the clonal dominance necessary for PNH to become clinically apparent. Herein, we report 2 patients with PNH whose PIGA-mutant cells had a concurrent, acquired rearrangement of chromosome 12. In both cases, der(12) had a break within the 3′ untranslated region of HMGA2, the architectural transcription factor gene deregulated in many benign mesenchymal tumors, that caused ectopic expression of HMGA2 in the bone marrow. These observations suggest that aberrant HMGA2 expression, in concert with mutant PIGA, accounts for clonal hematopoiesis in these 2 patients and suggest the concept of PNH as a benign tumor of the bone marrow.
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U2 - 10.1182/blood-2006-05-025148
DO - 10.1182/blood-2006-05-025148
M3 - Article
C2 - 16940417
AN - SCOPUS:33845494914
SN - 0006-4971
VL - 108
SP - 4232
EP - 4236
JO - Blood
JF - Blood
IS - 13
ER -