Discussion
TCF3-ZNF384 fusion gene resulting from a reciprocal translocation between chromosomes 19p13 (TCF3 ) and 12p13 (ZNF384 ) appears to be a distinct category. Bearing similarities toKMT2A- rearranged acute leukemias, these too present either as BCP-ALL or MPAL, B/myeloid type5 and are also associated with dim CD10 expression (pro-B immunophenotype) and upregulation of CD13 and/or CD331,2 as seen in our patient. About 2% blasts expressed myeloperoxidase, but the overall initial immunophenotype did not meet the required criteria for diagnosis of MPAL. Such diagnostic dilemmas with MPALs are frequent in routine practice and are also well-documented in the literature2. TCF3-ZNF384 -positive BCP-ALLs are associated with higher total leukocyte counts, poor response to steroids at day-8 and a relatively unfavourable outcome1. In our case too, the total leukocyte count showed a fivefold increase by day 8, with a significant increase in myeloblasts.
A lineage switch, i.e. conversion from lymphoid to myeloid immunophenotype (and exceptionally, vice versa ) in acute leukemias is a rare phenomenon. It occurs more often in pediatric leukemias, being reported mostly in patients with KMT2Are-arrangement6–8 but occasionally also in patients with ZNF384 -rearranged acute leukemias5,9. The lineage switch mostly occurs at the time of relapse. However, it is also reported in patients who have received either CD19-targeting agents or chimeric antigen receptor T-cell therapy7,8,10,11.
Various mechanisms may explain the lineage switch from lymphoid to myeloid or emergence of large myeloid clone following one week of high-dose steroid therapy in our case. It could simply represent the unmasking of a myeloid sub-clone that was initially outnumbered by the preponderant lymphoid blasts. This is supported by the presence of 2% myeloperoxidase-positive blasts at diagnosis. An alternative explanation might lie in the inherent plasticity of leukaemia stem cells for divergent differentiation12. The presence ofZNF384 translocation initially noted in the lymphoid blasts and subsequently shown to be present also in granulocytic cells may points towards the origin of this leukemia from a primitive hematopoietic precursor with divergent differentiation potential. In support of this theory, gene expression profiles of ZNF384- rearranged BCP-ALLs as well as B/myeloid MPALs have revealed enrichment of stem cell pathways.2 The stem cell origin probably leads to an initial development of acute leukemia with single lineage differentiation; but a therapeutic challenge may unravel its multi-lineage differentiation potential.
In conclusion,ZNF384- rearranged leukemias are a unique and possibly under-recognized category of neoplasms with multi-lineage differentiation potential. Both hematopathologists as well as hemato-oncologists should be aware of the potential lineage switch that may occur in this group of leukemias.
Conflict of interest statement: - All authors declare that they do not have any conflict(s) of interest(s) to declare.
Acknowledgement: The authors are thankful to Dr Mayur Parihar, Tata Medical Centre for performing FISH testing for TCF3-HLFtranslocation.