Molecular basis of clonal expansion of hematopoiesis in 2 patients with paroxysmal nocturnal hemoglobinuria (PNH).
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.
Inoue
Norimitsu
N
Department of Molecular Genetics, Osaka Medical Center for Cancer, Japan.
Izui-Sarumaru
Tomohisa
T
Murakami
Yoshiko
Y
Endo
Yuichi
Y
Nishimura
Jun-Ichi
J
Kurokawa
Ken
K
Kuwayama
Maki
M
Shime
Hiroaki
H
Machii
Takashi
T
Kanakura
Yuzuru
Y
Meyers
Gabrielle
G
Wittwer
Carl
C
Chen
Zhong
Z
Babcock
William
W
Frei-Lahr
Debra
D
Parker
Charles J
CJ
Kinoshita
Taroh
T
D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics*; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006461:Hemolysis / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D014408:Biomarkers, Tumor; D008565:Membrane Proteins; C080086:phosphatidylinositol glycan-class A protein