Primary Blasts from Infants with Acute Lymphoblastic Leukemia Cause Overt Leukemia in SOD Mice

Abstract

The establishment of an in vivo animal model system for infant acute lymphoblastic leukemia (ALL) would allow the testing of new agents against primary leukemic cells from infant ALL patients. We have demonstrated previously that growth of B-lineage leukemic cells in mice with severe combined immunodeficiency (SCID) was a significant prognostic factor for children with high risk ALL. We now have examined the significance of this prognostic variable for 13 infants with newly diagnosed ALL treated at participating institutions of the Children's Cancer Group (CCG). Chromosomal translocations were detected in 10/12 evaluated cases, including five with t(4;11), one each with t(7;9) and t(7;11), t(1;19), and t(9;22), and two with t(11;19). Twelve of the thirteen infants with ALL achieved remissions following induction chemotherapy. Primary leukemic cells from 8 of the 13 infants caused overt leukemia in SCID mice. Among these 8 SCID⁺ infants, 7 were CD1C⁻ and seven had cytogenetic or molecular evidence of an 11q23 rearrangement. Six of the 8 SCID⁺ infants have relapsed; only 2 remain in remission following chemotherapy or bone marrow transplant. However, among the 5 SCID⁻ infants there were also two relapses. These data are suggestive of a poorer outcome for SC1D⁺ infants, but larger numbers of patients must be analyzed to assess their statistical significance. In summary, we have established a SCID mouse model for human infant ALL that will be useful for 1) predicting short-term and long-term outcome of patients, 2) testing pharmacokinetics, efficacy, and toxicity of new agents, and 3) elucidating the in vivo mechanisms of chemotherapeutic drug resistance in infant ALL.

Key Words:

• Blasts
• infant ALL
• acute lymphoblastic leukemia
• leukemia in mice
• SCID mice