Donor Derived Acute Myeloid Leukaemia Following Allogeneic Cord Blood Transplantation: A Potential Role for RUNX1 and Down Syndrome Critical Region (DSCR) Genes.

Abstract 4300

Since the first allogeneic umbilical cord blood transplantation in 1988, there has been an increasing recognition and utilisation of cord blood as a source of haematopoietic stem cells. Donor cell leukaemia (DCL) following cord blood transplantation (CBT) remains a rarely reported phenomenon with only a handful of cases appearing in the literature to date. A plethora of possible mechanisms have been suggested for the development of DCL following CBT. In addition to the presence of undetected pre-leukaemic clones in the cord blood, chronic antigenic stimulation in an impaired tumour immune surveillance environment, perturbations of the host environment and premature ageing of the donor cells with associated chromosomal instability are among the proposed mechanisms for leukaemogenesis. Here we report a case of donor cell leukaemia in a 35-year-old female suffering from chronic myelogenous leukaemia. At 17 months following sex mismatched cord blood transplantation, donor cell derived BCR/ABL1 negative acute myeloid leukaemia (FAB M0) was diagnosed. In addition to the finding of monosomy 7, amplification of part of chromosome 21 containing the RUNX1, Down Syndrome Critical Region (DSCR) and ERG genes among others was identified by high-density array comparative genome hybridisation. The array findings were confirmed by qPCR and the RUNX1 amplification was mapped by FISH onto a marker chromosome, der(17)t(17;21)(p13;q?21). Importantly, these genetic changes were not found in the retrospectively tested cord blood cells using the same techniques. Whereas aberrations of chromosome 7 have been previously reported in cases of DCL post CBT, here we describe for the first time co-amplifications of several genes from the 21q22 chromosome region in conjunction with the finding of monosomy 7. RUNX1 amplifications are known to occur in acute leukaemia of both myeloid and lymphoid lineage. Gains of the 21q22 region with multiple copies of RUNX1 gene have been associated with therapy related AML and MDS, but thus far has not been reported in the context of DCL following CBT. Furthermore, the possibility that additional genomic imbalances may have contributed to the pathogenesis of DCL in this case is also raised. Co-amplification of genes from the DSCR at 21q22 in the presence of unmutated GATA1 and JAK3 genes may be relevant in this context, as located within this region are genes with powerful effects on differentiation (such as DYRK1A) and several genes whose over-expression has been linked with disturbed megakaryopoiesis and myeloproliferation including miR155, BACH1, RCAN1 (DSCR1), RUNX1 and ERG. In addition to the classical genomic imbalances such as monosomy 7 that typify the genetic makeup of secondary AML, this case highlights for the first time the potential cooperative role of oncogenic co-amplification in the pathogenesis of donor cell leukaemia.