Emergence of a prominent myeloid clone in a ZNF384‐rearranged B‐cell precursor acute lymphoblastic leukaemia post‐corticosteroid pre‐phase therapy

Abstract

To the Editor: ZNF384 (zinc finger protein 384) rearrangements are recently recognized cytogenetic abnormalities. Forty-eight percent of mixedphenotype acute leukaemia (MPAL), B/myeloid 1 and 4% of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) 2 show this rearrangement. Several fusion partners of ZNF384 have been described, the most common being TCF3 and EP300, but also include ESWR1, TAF15, CREBBP, ARID1B, SYNRG and BMP2K. 1-3 We report a challenging case with TCF3-ZNF384 rearrangement that initially presented as BCP-ALL but showed the emergence of a large myeloid blast subset following 1 week of high-dose steroid therapy. A 2-year-old female presented with fever and pallor of 1 week duration. Examination revealed mild hepatomegaly and splenomegaly. The haemoglobin was 46 g/L, platelet count 14.0 × 10 9 /L and total leukocyte count 14.7 × 10 9 /L. Peripheral blood film showed 62% blasts (Figure 1A,B). Bone marrow aspiration revealed 82% blasts without Auer rods but with cytochemical myeloperoxidase (MPO) positivity in 2% of the blasts. On flow cytometry, the blasts expressed bright CD19, cytoplasmic CD79a, cytoplasmic CD22 and CD33, along with dim expression of CD10 and CD13 (Figure S1). However, cytoplasmic myeloperoxidase (anti-MPO) expression was absent. Fluorescent in situ hybridisation (FISH) testing with dual-colour dual-fusion probes for BCR-ABL1 and ETV6-RUNX1, and dual-colour break-apart probes for KMT2A and TCF3 (CytoTest Inc. Rockville, MD, USA) revealed presence of TCF3 translocation in 80% of cells (Figure 1E). TCF3-PBX1 and TCF3-HLF translocations were excluded using a tri-colour probe (Cytocell Ltd, Cambridge). In view of absence of metaphase, further FISH testing was performed using a commercially available dual-colour break-apart probe (ZytoVision GmbH, Germany) that confirmed rearrangement of ZNF384 (Figure 1G). A diagnosis of BCP-ALL with TCF3-ZNF384 [t(12;19)(p13;p13)] rearrangement was rendered, following which the child was initiated on the standard-risk BCP-ALL protocol of the Indian Childhood Collaborative Leukaemia Group (ICiCLe), comprising a prephase of prednisolone 60 mg/m 2 /day in three divided doses. 4

ZNF384-Related Fusion Genes in Acute Lymphoblastic Leukemia

“…This confirms that patients with TCF3-ZNF384 showed a poor response to steroid. 3,61 Further, Oberley et al reported that two patients with TCF3-ZNF384 relapsed after 10 years. 6 The inherent plasticity of leukemia stem cells causes divergent differentiation.…”

Leukemia With TCF3-ZNF384 Rearrangement as a Distinct Subtype of Disease With Distinct Treatments: Perspectives From A Case Report and Literature Review

“…Later, it was reported to be present in multiple pediatric B-ALL and B/M MPAL cases. We reviewed the literature and found 43 cases of BCP-ALL (including this case) and 9 cases of MPAL with detailed clinical data, as shown in Supplementary Table3(4)(5)(6)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Only one adult B-ALL case has been reported.…”