Case Report: Whole genome sequencing identifies CCDC88C as a novel JAK2 fusion partner in pediatric T-cell acute lymphoblastic leukemia

Abstract

In the present report, we applied whole genome sequencing (WGS) to genetically characterize a case of pediatric T-cell acute lymphoblastic leukemia (ALL) refractory to standard therapy. WGS identified a novel JAK2 fusion, with CCDC88C as a partner. CCDC88C encodes a protein part of the Wnt signaling pathway and has previously been described in hematological malignancies as fusion partner to FLT3 and PDGFRB. The novel CCDC88C::JAK2 fusion gene results in a fusion transcript, predicted to produce a hybrid protein, which retains the kinase domain of JAK2 and is expected to respond to JAK2 inhibitors. This report illustrates the potential of WGS in the diagnostic setting of ALL.

Feasibility to use whole-genome sequencing as a sole diagnostic method to detect genomic aberrations in pediatric B-cell acute lymphoblastic leukemia

“…Beyond the established genetic subgroups, the detection of novel genetic lesions in ALL is becoming rapidly relevant, as potentially targetable (13, 16) or lesions affecting outcome have been described (7,8,(10)(11)(12)(13)(14)(15)(16)(51)(52)(53)(54)(55). The present approach enabled the identification of at least one potentially class-defining lesion in the majority of B-other ALL (35/39) samples.…”

“…The aberrations mandatory to investigate according to the current ALL treatment trial protocol (48) were all selected, as were the genes/genomic regions included in the UKALL-CNA classifier and IKZF1+ profiles (49,50). Furthermore, the key genes signaling genetic subtypes with potential diagnostic or therapeutic implications among B-other ALL (10)(11)(12)(13)(14)(15)(16)(51)(52)(53)(54)(55) or included in WHO 2022 classification (8) or the ICC of hematological malignancies were also included (9). The genes' IDs and genomic coordinates are listed in Supplementary Table 2.…”

“…Based on these new findings, the latest WHO 2022 classification (8) and the International Consensus Classification (ICC) (9) propose a number of emerging ALL subgroups among B-cell ALL, significantly decreasing the number of patients lacking primary genetic lesion, the so-called B-other ALL. While these novel aberrations are not yet mandatory to investigate in contemporary treatment protocols, these genetic lesions have been suggested to impact outcomes and may thereby contribute valuable information to patient management (10)(11)(12)(13)(14)(15)(16).…”