Molecular characteristics of terminal deoxynucleotidyl transferase negative precursor B‐cell phenotype Burkitt leukemia with IGH‐MYC rearrangement

Abstract

Precursor B cell phenotype Burkitt lymphoma/leukemia with IGH-MYC is a rare subtype of Burkitt lymphoma (BL). BL and B lymphoblastic leukemia/lymphoma (B-ALL/ LBL) differ as regards treatment and the distinction between these two entities is crucial. Patients demonstrating a terminal deoxynucleotidyl transferase (TdT)-positive precursor B cell phenotype with IGH-MYC rearrangement have been reported to be molecularly distinct from BL and closer to B-ALL/LBL. We investigated the molecular characteristics of two cases of a rare but distinct TdT-negative precursor B cell phenotype BL. Both patients showed FAB L3 morphology with IGH-MYC translocation, but had precursor B cell immunophenotypes including dim to moderate expression of CD45 and absence of BCL6, CD20, monoclonal kappa, and lambda light chain expression. To characterize the molecular features, we performed exome sequencing and analyzed the breakpoint junction of the IGH-MYC rearrangement. We detected KMT2D mutations in both cases, a rarely acquired chromatin modifying gene mutation in BL. The breakpoint analysis revealed that the IGH-MYC rearrangement occurred due to an aberrant VDJ recombination in one case. The treatment protocols differed, including high-grade lymphoma treatment and standard B-ALL treatment.Complete remission was achieved in the patient who received B-ALL treatment. The degree of resemblance of BL and B-ALL differed between two cases, but the molecular pathogenesis and manifesting features of both TdT-negative precursor B cell phenotype BL case were distinct from classic BL, which indicates the need for a better understanding of this uncommon entity that does not fit in current diagnostic and classification categories. K E Y W O R D S B lymphoblastic leukemia/lymphoma, Burkitt lymphoma, MYC

Burkitt leukemia with precursor B-cell features that developed after ruxolitinib treatment in a patient with hydroxyurea-refractory <i>JAK2</i>^V617F-myeloproliferative neoplasm

“…Taken together with the IGHJ3 breakpoint on the IGH side, t(8;14)(q24;q32)/MYC-IGH in this case likely occurred at an early B-cell stage in the BM, in contrast to t(8;14)(q24;q32)/MYC-IGH in the majority of cases of sporadic BL that occurred in GC. Nevertheless, as reported MYC breakpoints were distributed over a large region encompassing the MYC coding exons (Table 1), 2,4 further studies are required to confirm the validity of the CpG breakage model in precursor B-cell BL.…”

“…Although precursor B-cell BL has been described primarily in the pediatric literature, 6,7 this report confirmed that this rare type of BL can occur in the adult population (Supplementary Table S1). [1][2][3][4][5]8,9 As t(8;14)(q24;q32)/MYC-IGH breakpoints in sporadic cases of BL occur nearby or within MYC exon 1, which is a target of somatic hypermutation (SHM), 20 and within the switch regions of IGH, the translocation has been considered to be mediated by the SHM/class switch recombination (CSR) mechanism in the GC. 1,2 However, as BL cells of this case exhibited a precursor B-cell immunophenotype and carried unmutated IGH V-D-J sequences, it is unlikely that the SHM/CSR machinery was active.…”

“…In accordance with this, the breakpoint occurred at the IGHJ3 segment and an N-segment was inserted at the junction, indicating that aberrant V-D-J recombination activity within BM was responsible for the breakage and joining of the IGH side of the translocation; the same held true for IG-MYC breakpoints of precursor B-cell BL cases reported previously (Table 1). 2,4 On the other hand, potential mechanisms involved in the breakpoints of the partner genes have been proposed. 21 The CpG-type breakage is observed in BCL2 breakpoints of t(14;18)(q32;q21)/IGH-BCL2, 22 MALT1 breakpoints of t(14;18)(q32;q21)/IGH-MALT1, 23 and a fraction of CCND1 breakpoints of t(11;14)(q13;q32)/CCND1-IGH, 24 all of which are considered to develop in the pro-B/pre-B-cell stage of B-cell differentiation.…”

“…In accordance with this, the breakpoint occurred at the IGHJ3 segment and an N-segment was inserted at the junction, indicating that aberrant V-D-J recombination activity within BM was responsible for the breakage and joining of the IGH side of the translocation; the same held true for IG- MYC breakpoints of precursor B-cell BL cases reported previously ( Table 1 ). 2 , 4 …”

“…1 Although leukemia cells of BL typically express cell surface IG μ heavy chain (IgM) with a restrictive light chain, B-cell antigens, and germinal center (GC) markers, 1 small fractions of both pediatric and adult cases have a precursor B-cell phenotype, i.e., expression of TdT and sometimes CD34, and absence of CD20 and surface IG expression (Supplementary Table S1). [1][2][3][4][5][6][7][8][9] Whether there is an increased risk of developing lymphoproliferative disorders in patients with myeloproliferative neoplasm (MPN) remains controversial. [10][11][12][13][14] Reported lymphoid neoplasms include both T-cell and B-cell tumors and a wide range of histopathological subtypes.…”