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.