Gene Therapy

Gene therapy for X-linked severe combined immunodeficiency syndrome (X-SCID) has led to activation of the LMO2 gene.42'43 Two of ten patients who received retrovirus vector-mediated gene transfer for X-SCID developed T-cell ALL. This was caused by insertion of the retroviral vector with LMO2 gene activation, leading to leukemic transformation. In normal hematopoiesis, CD34-positive cells may develop into all hematopoietic cell lines. In the lym-phoid series, these may differentiate into either B cells or T cells. Ex vivo infection of hematopoietic stem cells by the retrovirus encoding IL2 R gamma c is followed by reinfusion, and it results in activated chromosome translocations with LMO2, including t(ll;14)(p13;q11), or t(7;11)(q35;p13). This represents a classic activation of signaling pathways by the retrovirus-transformed cells leading to T-cell ALL.42-44

In adults with ALL, abnormalities of cell cycle regulatory genes are frequently present and may be determinants in leukemogenesis. These include the retinoblastoma gene (Rb), p53, p15 (INK4B), and p16 (INK4A).45 Pui has detailed and elucidated the initial abnormalities, chromosome aberrations, and their cell signaling consequences in a comprehensive review of ALL, with detailed genomic pathways.1033

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