B-Lymphoblastic Lymphomas Evolving from Follicular Lymphomas Co-Express Surrogate Light Chains and Mutated Gamma Heavy Chains

Abstract

Follicular lymphoma (FL) is an indolent B-cell non-Hodgkin lymphoma able to transform into germinal center-type diffuse large B-cell lymphoma. We describe four extraordinary cases of FL, which progressed to TdTCD20 precursor B-lymphoblastic lymphoma (B-LBL). Fluorescence in situ hybridization analysis showed that all four B-LBLs had acquired a MYC translocation on transformation. Comparative genomic hybridization analysis of one case demonstrated that in addition to 26 numerical aberrations that were shared between the FL and B-LBL, deletion of CDKN2A/B and 17q11, 14q32 amplification, and copy-neutral loss of heterozygosity of 9p were gained in the B-LBL cells. Whole-exome sequencing revealed mutations in FMN2, NEB, and SYNE1 and a nonsense mutation in KMT2D, all shared by the FL and B-LBL, and TNFRSF14, SMARCA2, CCND3 mutations uniquely present in the B-LBL. Remarkably, all four FL-B-LBL pairs expressed IgG. In two B-LBLs, evidence was obtained for ongoing rearrangement of IG light chain variable genes and expression of the surrogate light chain. IGHV mutation analysis showed that all FL-B-LBL pairs harbored identical or near-identical somatic mutations. From the somatic gene alterations found in the IG and non-IG genes, we conclude that the FLs and B-LBLs did not develop in parallel from early t(14;18)-positive IG-unmutated precursors, but that the B-LBLs developed from preexistent FL subclones that accumulated additional genetic damage.

Dramatic increase in gene mutational burden after transformation of follicular lymphoma into TdT+ B-lymphoblastic leukemia/lymphoma

“…Not only did the B-ALL/LBL follow the FL within 1 yr without any mutagenic therapy, but there were at least three pathogenic translocations, two of which (BCL2 and BCL6) overlapped between the FL and B-ALL/LBL. The addition of the MYC rearrangement matches all other cases of B-ALL/LBL transformed from FL (Geyer et al 2015;Slot et al 2016) and a clonal relationship between FL and B-ALL/LBL was established in all of these cases. Moreover, mechanistic roles for MYC in oncogenesis, genetic instability, aggressive transformations of lymphomas, and transdifferentiation have been previously demonstrated and further support this rearrangement as an important contributor to LL transformation (Okosun et al 2014;Pasqualucci et al 2014;Francesconi et al 2019).…”

“…The B-ALL/LBL transformation was ultimately followed by the patient's demise within the following year. This aggressive clinical course appears to be typical in the patients with FL-B-ALL/LBL progression (Geyer et al 2015;Slot et al 2016).…”

“…Therefore, it has suggested that transformed malignant tumors such as these be alternatively referred to as highgrade B-cell lymphoma with blastic features and TdT-expression (Ok et al 2019). However, based on the progenitor B-cell phenotype and blastic morphology, we have chosen to call this case a transformation of FL to B-ALL/LBL, as typically done by others (Geyer et al 2015;Slot et al 2016) to follow the current WHO 2017 classification (Swerdlow et al 2017).…”

“…The rearrangement involving MYC, a potent oncogene, most likely played a key role in this transformation. MYC translocations are well-known to contribute to high aggressiveness of lymphomas and are a hallmark of FL-B-ALL/LBL transformation (Voorhees et al 2004;Young et al 2008;Geyer et al 2015;Slot et al 2016;Li et al 2018). Interestingly, single-cell RNA-seq data in murine models have shown that MYC activity can predict reprogramming efficiency across many somatic cell types (Francesconi et al 2019), emphasizing a potential element of "dedifferentiation" in these transformations.…”

“…Most cases of FL transformation result in diffuse large B-cell lymphoma, but, rarely, lymphoblastic lesions comprised of immature rather than mature B cells can arise, typically in younger patients (De Jong et al 1988;Gauwerky et al 1988;Kroft et al 2000;Sun et al 2002;Young et al 2008). Although the mechanisms underlying transformation to diffuse large B-cell lymphoma have been extensively examined (Rossi et al 2006;Pasqualucci et al 2014), molecular characterization of the "dedifferentiation" to Blymphoblastic leukemia/lymphoma (B-ALL/LBL) has been very limited thus far (Geyer et al 2015;Slot et al 2016). Here we present a case of an FL transformed into B-cell B-ALL/LBL with extensive molecular characterization including analysis of the somatic hypermutation (SHM) status of the immunoglobulin (Ig) genes, cytogenetic studies, and whole-exome sequencing (WES) of the patient's normal, FL, and B-ALL/LBL tissues.…”