Clonal Expansion in Paroxysmal Nocturnal Hemoglobinuria (PNH): Expression of Mutant HMGA2 Suggests That PNH Is a Benign Tumor of the Bone Marrow.

In PNH, a somatic mutation of PIGA in hematopoietic stem cells causes the deficiency of glycosylphosphatidylinositol-anchored proteins (GPI-AP), but the basis of clonal expansion of the PIGA-mutant cells is speculative. Because some patients with aplastic anemia develop PNH, GPI-AP deficient stem cells may have a survival advantage in the setting of immune-mediated bone marrow injury. However, in many patients with aplastic anemia, the GPI-AP deficient cell populations remain small or disappear. Therefore, we hypothesized that additional abnormalities in the PIGA-mutant stem cells account for clonal expansion. We previously reported a patient with PNH/aplastic anemia (J20) whose PIGA-mutant hematopoietic cells had a coexistent cytogenetic abnormality [46,XX,ins(12;12)(q14;q12q14)]. In this patient, the insertion disrupted the 3′ untranslated region of HMGA2, an architectural transcription factor whose aberrant expression causes benign mesenchymal tumors. Truncated HMGA2 transcripts lacking the acidic tail (the pathophysiologically relevant form) were identified in the double mutant cells. In the present study, we characterized a similar genetic abnormality in a patient with classical PNH. In this case, PIGA-mutant cells again had a concurrent der(12) [46,XX,ins(12)(p13q14q13)]. A 20 Mbp fragment from 12q13 to q14 and a 300bp fragment from 12q14 together containing exons 1–4 and part of exon 5 of HMGA2 were inserted inversely and directly, respectively, into intron 1 of TEL at 12p13. One of the breakpoints in the HMGA2 locus was at almost the same position as the HMGA2 breakpoint in patient J20. Truncated HMGA2 transcripts (lacking the acidic tail) were highly expressed in bone marrow cells. Full-length transcripts of TEL without any fusion partners were normally expressed and no other transcription units were disrupted by the breakpoints. That similar cytogenetic abnormalities were observed in these two patients suggests that aberrant expression of HMGA2, in concert with mutant PIGA, accounted for the clonal expansion and explains the benign tumor characteristics of PNH.