Molecular Basis of Clonal Expansion of Hematopoiesis in 2 Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2006 Aug 31

PMID 16940417

Citations 52

Authors

Norimitsu Inoue

Tomohisa Izui-Sarumaru

Yoshiko Murakami

Yuichi Endo

Jun-Ichi Nishimura

Ken Kurokawa

Maki Kuwayama

Hiroaki Shime

Takashi Machii

Yuzuru Kanakura

Gabrielle Meyers

Carl Wittwer

Zhong Chen

William Babcock

Debra Frei-Lahr

Charles J Parker

Taroh Kinoshita

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Case report: Immune pressure on hematopoietic stem cells can drastically expand glycosylphosphatidylinositol-deficient clones in paroxysmal nocturnal hemoglobinuria.

Shingai N, Mizumaki H, Najima Y, Yamada Y, Tran D, Haraguchi K Front Immunol. 2024; 14:1329403.

PMID: 38288112 PMC: 10822943. DOI: 10.3389/fimmu.2023.1329403.

Cellular carcinogenesis in preleukemic conditions:drivers and defenses.

Ueda K, Ikeda K Fukushima J Med Sci. 2023; 70(1):11-24.

PMID: 37952978 PMC: 10867434. DOI: 10.5387/fms.2023-17.

Paroxysmal Nocturnal Hemoglobinuria: Biology and Treatment.

Bravo-Perez C, Guarnera L, Williams N, Visconte V Medicina (Kaunas). 2023; 59(9).

PMID: 37763731 PMC: 10535188. DOI: 10.3390/medicina59091612.

Case 14: A 37-Year-Old Pregnant Woman With Thrombocytopenia.

Kim T, Lee J, Jeon Y J Korean Med Sci. 2023; 38(36):e318.

PMID: 37698212 PMC: 10497352. DOI: 10.3346/jkms.2023.38.e318.

Long noncoding RNA FAM157C contributes to clonal proliferation in paroxysmal nocturnal hemoglobinuria.

Wang H, Liu H, Li L, Chen Y, Liu Z, Li L Ann Hematol. 2023; 102(2):299-309.

PMID: 36607351 PMC: 9889514. DOI: 10.1007/s00277-022-05055-8.

References

ARLOTTA P, Tai A, Manfioletti G, Clifford C, Jay G, Ono S . Transgenic mice expressing a truncated form of the high mobility group I-C protein develop adiposity and an abnormally high prevalence of lipomas. J Biol Chem. 2000; 275(19):14394-400. DOI: 10.1074/jbc.m000564200. View

Sugimori C, Chuhjo T, Feng X, Yamazaki H, Takami A, Teramura M . Minor population of CD55-CD59- blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia. Blood. 2005; 107(4):1308-14. DOI: 10.1182/blood-2005-06-2485. View

Baldassarre G, Fedele M, Battista S, Vecchione A, Klein-Szanto A, Santoro M . Onset of natural killer cell lymphomas in transgenic mice carrying a truncated HMGI-C gene by the chronic stimulation of the IL-2 and IL-15 pathway. Proc Natl Acad Sci U S A. 2001; 98(14):7970-5. PMC: 35452. DOI: 10.1073/pnas.141224998. View

Borrmann L, Wilkening S, Bullerdiek J . The expression of HMGA genes is regulated by their 3'UTR. Oncogene. 2001; 20(33):4537-41. DOI: 10.1038/sj.onc.1204577. View

Fedele M, Battista S, Manfioletti G, Croce C, Giancotti V, Fusco A . Role of the high mobility group A proteins in human lipomas. Carcinogenesis. 2001; 22(10):1583-91. DOI: 10.1093/carcin/22.10.1583. View

Reeves R . Molecular biology of HMGA proteins: hubs of nuclear function. Gene. 2001; 277(1-2):63-81. DOI: 10.1016/s0378-1119(01)00689-8. View

Hess J, Kossev P . Molecular genetics of benign tumors. Cancer Invest. 2002; 20(3):362-72. DOI: 10.1081/cnv-120001182. View

Frickhofen N, Heimpel H, Kaltwasser J, Schrezenmeier H . Antithymocyte globulin with or without cyclosporin A: 11-year follow-up of a randomized trial comparing treatments of aplastic anemia. Blood. 2002; 101(4):1236-42. DOI: 10.1182/blood-2002-04-1134. View

Inoue N, Murakami Y, Kinoshita T . Molecular genetics of paroxysmal nocturnal hemoglobinuria. Int J Hematol. 2003; 77(2):107-12. DOI: 10.1007/BF02983208. View

10.

Ashar H, Tkachenko A, Shah P, Chada K . HMGA2 is expressed in an allele-specific manner in human lipomas. Cancer Genet Cytogenet. 2003; 143(2):160-8. DOI: 10.1016/s0165-4608(03)00037-2. View

11.

Tessari M, Gostissa M, Altamura S, Sgarra R, Rustighi A, Salvagno C . Transcriptional activation of the cyclin A gene by the architectural transcription factor HMGA2. Mol Cell Biol. 2003; 23(24):9104-16. PMC: 309667. DOI: 10.1128/MCB.23.24.9104-9116.2003. View

12.

Beillard E, Pallisgaard N, van der Velden V, Bi W, Dee R, van der Schoot E . Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using 'real-time' quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR) - a Europe against cancer program. Leukemia. 2003; 17(12):2474-86. DOI: 10.1038/sj.leu.2403136. View

13.

Hollander N, Selvaraj P, Springer T . Biosynthesis and function of LFA-3 in human mutant cells deficient in phosphatidylinositol-anchored proteins. J Immunol. 1988; 141(12):4283-90. View

14.

Rotoli B, Luzzatto L . Paroxysmal nocturnal haemoglobinuria. Baillieres Clin Haematol. 1989; 2(1):113-38. DOI: 10.1016/s0950-3536(89)80010-1. View

15.

Miyata T, Takeda J, Iida Y, Yamada N, Inoue N, Takahashi M . The cloning of PIG-A, a component in the early step of GPI-anchor biosynthesis. Science. 1993; 259(5099):1318-20. DOI: 10.1126/science.7680492. View

16.

Takeda J, Miyata T, Kawagoe K, Iida Y, Endo Y, Fujita T . Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell. 1993; 73(4):703-11. DOI: 10.1016/0092-8674(93)90250-t. View

17.

Grosschedl R, Giese K, Pagel J . HMG domain proteins: architectural elements in the assembly of nucleoprotein structures. Trends Genet. 1994; 10(3):94-100. DOI: 10.1016/0168-9525(94)90232-1. View

18.

Hillmen P, Lewis S, Bessler M, Luzzatto L, Dacie J . Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995; 333(19):1253-8. DOI: 10.1056/NEJM199511093331904. View

19.

Kawagoe K, Kitamura D, Okabe M, Taniuchi I, Ikawa M, Watanabe T . Glycosylphosphatidylinositol-anchor-deficient mice: implications for clonal dominance of mutant cells in paroxysmal nocturnal hemoglobinuria. Blood. 1996; 87(9):3600-6. View

20.

Nishimura J, Inoue N, Azenishi Y, Hirota T, Akaogi T, Shibano M . Analysis of PIG-A gene in a patient who developed reciprocal translocation of chromosome 12 and paroxysmal nocturnal hemoglobinuria during follow-up of aplastic anemia. Am J Hematol. 1996; 51(3):229-33. DOI: 10.1002/(SICI)1096-8652(199603)51:3<229::AID-AJH8>3.0.CO;2-Z. View