Table 2.
Clonal expansion, myelodysplasias, and transformation
| Patient/disease/transgene | Relevant vector sequences (references) | Secondary effect (mo after treatment) | Genomic insertion sites (transcript status) | Other genetic alterations (mo after treatment) | Reference(s) |
|---|---|---|---|---|---|
| P4/SCID-X1/γC | MFG(B2), Moloney-MLV LTR (8,138) | T-ALL, mature T cell (30) | LMO2 (↑) | Translocation(6,13); CDKN2A deletion | 3,139 |
| P5/SCID-X1/γC | T-ALL, late cortical T cell (34) | LMO2 (↑) | SIL-TAL microdeletion, trisomy 10, Notch mutation (1593F/S) | 139 | |
| P7/SCID-X1/γC | T-ALL, late cortical T cell (68) | CCND2 (↑) | CDKN2A deletion | 42,139 | |
| P10/SCID-X1/γC | T-ALL, late cortical T cell (33) | LMO2 (↑), BMI1 (↑) | Notch mutation (1707A/P) | 42,139 | |
| P1/X-CGD/gp91phox | SFFV LTR (9,16) | Multiple predominant progenitor cell clones (5), subsequent oligoclonal hematopoiesis, monosomy 7 (21), MDS (27) | MDS1-EVI1 (↑), PRDM16 (=), SETBP1 (↑) | CpG methylation in promoter of the viral LTR (9); CDKN2B and p15INK4B hypermethylation; phosphorylation of H2AX and DNA double-strand breaks (27) | 16,32 |
| P2/X-CGD/gp91phox | Multiple predominant progenitor cell clones (5), subsequent oligoclonal hematopoiesis, monosomy 7 (33), MDS (43) | MDS1-EVI1 (↑), PRDM16 (↑) | CpG methylation in promoter of the viral LTR (15); CDKN2B and p15INK4B hypermethylation; phosphorylation of H2AX and DNA double-strand breaks (43) | 16,32 | |
| P8/SCID-X1/γC | MFG, Moloney-MLV LTR (8,140) | T-ALL (24) | LMO2 (↑) | Notch1 mutation (gain-of-function, 1559R/P), CDKN2A deletion, TCRb/STIL-TAL1 translocation | 41 |
| P2/Thalassemia/β(T87Q)-globin | ΔU3 HIV LTR + 2xcHS4 insulators (24,141) | Dominant, myeloid-biased cell clone | HMGA2 (↑) | Vector rearrangement; transcriptional activation of HMGA2 in erythroid cells with increased expression of a truncated HMGA2 mRNA insensitive to degradation by let-7 micro-RNAs | 24 |