Final Diagnosis
B-ALL with KMT2A::CBL fusion
Discussion
KMT2A, previously known as MLL, is a histone H3 lysine 4 (H3K4) methylase. Translocations involving the KMT2A gene located at band 11q23 with various partner chromosomes have been recurrently reported in acute leukemias in infants, children, and adults[1, 2]. In fact, approximately 10% of acute leukemias harbor KMT2A rearrangements[3]. Further, KMT2A rearrangements typically are associated with poor prognosis, while very few confer intermediate to good prognosis in acute leukemias[1, 4]. Seven genes account for over 90% of the fusion partners with KMT2A in acute leukemias; these include AFF1, MLLT3, MLLT1, MLLT10, AFDN, KMT2A -PTDs (partial tandem duplications) and ELL[2]. A wider range of rare fusion partners account for the remaining 10%, with relatively less known about the fusion partners and disease mechanisms, especially for cases of ALL, which has been less studied compared to AML[3].
The major breakpoint cluster region involved in 98% of KMT2A rearrangements, including the current case presented, is between intron 7 and exon 13, while the minor breakpoint cluster region is between intron 20 and exon 24[2]. Specific breakpoint location has been shown to correlate with fusion partners, patient age, leukemia lineage, cancer biology, and prognosis, with breakpoints in KMT2A intron 11 associated with worse prognosis[2].
While reciprocal chromosome translocations involving KMT2A are relatively common with known prognostic significance in acute leukemias, KMT2A::CBL fusions are extremely rare events and have been identified in few cases of leukemias of different lineages. B-ALL with KMT2A::CBL fusion has been reported in one patient [5]. Further, the close physical proximity of KMT2A and CBL on the 11q23.3 locus may potentially lead to failure to detect this rearrangement using the conventional FISH break-apart probes[5, 6].
CBL, encoding a RING finger E3 ubiquitin ligase, is a proto-oncogene involved in negative regulation of tyrosine kinase receptor signaling pathways, with CBL mutations identified in hematologic, mainly myeloid, malignancies and few reports in ALL[5-9]. Little is known about the prognostic significance of KMT2A::CBL fusions given the limited number of reported cases. However, of note, two of seven reported cases were secondary neoplasms with both patients receiving prior chemotherapy[5]. The current case represents a primary malignancy in a previously healthy child with good initial response to chemotherapy. The leukemic cells in this case also showed a concurrent loss of part of PAX5, a gene which is frequently deleted in B-ALL. PAX5 encodes the B-cell lineage transcription factor paired box (PAX) 5 involved in B-cell differentiation and maintenance of mature B cell function[10-12].
The mechanism of KMT2A::CBL leukemogenesis is not well established. Typically, rearrangements involving KMT2A lead to deletion of the methyltransferase domain and fusion of KMT2A to a gene involved in transcription elongation[3]. Dysregulation of histone methylation with changes in histone methylation patterns of KMT2A target genes leads to upregulation of leukemia-related genes, including HOXA genes[13]. However, investigation of specific fusion proteins has revealed cases of leukemia occurring independently of HOXA transcriptional activation, suggesting distinct entities and mechanisms associated with different fusion partners[3]. Further work is needed to characterize the pathologic mechanisms involved in leukemogenesis with KMT2A::CBL fusion.
In conclusion, this case demonstrates a rare KMT2A::CBL fusion in pediatric B-cell acute lymphoblastic leukemia. Atypical FISH patterns may indicate KMT2A rearrangement, however precise detection of breakpoints within the coding regions of the KMT2A and CBL genes by microarray analysis enabled identification of a rare rearrangement. This case also highlights the importance of the utilization of both microarray and FISH in the cytogenetic evaluation of acute leukemias, with awareness of the limitations of each testing technique. Additional study is needed to further elucidate the leukemogenic mechanisms and prognostic significance of the KMT2A::CBL fusion in acute leukemia.
References
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