Abstract Abstract 3470 Hematopoiesis is traditionally seen as the unidirectional maturation of stem cells into lineage committed cells. Recent data are suggestive for some degree of lineage flexibility in both normal as malignant cells. We here present a boy that presented with T-cell acute lymphoblastic leukemia (T-ALL). During T-ALL treatment, the patient developed in short time a non-Langerhans-cell histiocytose in the ileum, and subsequently a disseminated form of histiocytic sarcoma (a.o. also in the liver). Interestingly, the same clonal T cell receptor (TCR) gene rearrangements were found in all three malignancies (TCRB-VJ, TCRG-VJ and TCRB-DJ) indicating they were related. There were no immunoglobulin rearrangements. To understand the evolution from T-ALL to non-Langerhans-cell histiocytose and to histiocytic sarcoma, an extensive genetic analysis was performed. Using a SNP6.0 array platform we analyzed DNA isolated from T-ALL cells, a bone marrow sample obtained during complete remission from theT-ALL, a biopsy from the ileum tumor, the liver tumor, and DNA isolated from skin fibroblasts. The three tumor samples were not fully concordant in the SNP analysis, with lesions acquired but also absent from subsequent samples. All three tumor samples showed identical TCR gene rearrangements as well as a loss of the CDKN2A/B region, the only gene-containing copy number aberration (CNA) present in the T-ALL. The T-ALL sample showed a homozygous loss of the CDKN2A/B region, whereas both the ileum and liver samples showed a heterozygous loss. In addition, the three tumor samples shared two 1Mb regions of loss of heterozygosity (LOH) on chromosomes 6p and 11p, containing DDB2, MADD and RUNX2, amongst others. A gain on chromosome 19q containing 12 genes was shared between the ileum and liver sample only. In addition, the ileum tumor showed 14 non-shared CNAs of which 11 losses, 2 homozygous losses, and 1 gain, affecting 11 genes including ZFAT, PTPRK and beta-catenin (CTNNB1). The liver tumor acquired gains of a large part of chromosome 5, the p-arm of chromosome 11 and the q-arm of chromosome 22 reminiscent of a chromothrypsis event. The PAX5 gene indicated in the progression of an ALL to histiocytic sarcoma was not affected in either of the samples. These results indicate that the three tumors are related but did not evolve from each other in a linear manner. Apparently, the common oncogenetic transformation occurred at an early differentiation stage with lineage plasticity, i.e. with some lineage specification but without full lineage commitment. Disclosures: No relevant conflicts of interest to declare.