The evolving contribution of hematopoietic progenitor cells to lymphomagenesis

Abstract

Recent genomic studies have outlined a landscape of recurrent alterations within some subtypes of lymphoid cancer. Yet, the timing and cellular contexts during which these alterations occur (ie, the molecular ontogeny) remain poorly understood. Lymphoid malignancies offer an exceptional opportunity to delineate the ontogeny of somatic alterations, as lymphocyte differentiation absolutely requires the introduction of indelible genetic rearrangements at antigen receptor loci during specific stages of maturation. We review competing models of lymphomagenesis and highlight evolving evidence that somatic alterations in uncommitted hematopoietic progenitors contribute to some mature lymphoid neoplasms. These progenitors could serve as reservoirs for further clonal evolution and thereby contribute to therapeutic resistance, tumor relapse, and the development of second hematologic malignancies. Defining the pathways that are dysregulated within early progenitors and the ontogeny of subsequent alterations that contribute to lymphoid transformation could establish novel therapeutic targets across a variety of hematologic malignancies and even guide avenues for future preventive strategies. (Blood. 2012; 120(13):2553-2561) Introduction B-cell and T-cell lymphomas compose Ͼ 90% of lymphoid malignancies worldwide and 4% of new cancers each year. 1 Recent studies have catalogued hundreds of genetic and transcriptional alterations across large panels of lymphomas, with extensive representation of the 2 most common subtypes, follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). [2][3][4][5][6][7][8][9][10][11] Within a short period, the large majority of lymphoma-associated alterations will probably be known, leaving 2 great challenges. The first is to clarify which alterations functionally contribute to the lymphoma phenotype. The second challenge is to define the clonal architecture of individual lymphomas, including the cellular contexts in which each alteration develops (ie, the molecular ontogeny).New insights from both hematologic and epithelial tumors indicate that malignancies can harbor extensive clonal heterogeneity across multiple stages of differentiation. [12][13][14][15][16][17] However, the investigation of ontogeny in nonlymphoid cancers requires the use of surrogates for differentiation stage, such as immunophenotype, which are inherently variable (eg, through epigenetic plasticity). In contrast, lymphocyte differentiation absolutely requires the introduction of indelible genetic alterations at antigen receptor loci. Like all hematopoietic cells, lymphocytes derive from hematopoietic stem cells (HSCs) through a process of lineage-specific differentiation that is orchestrated by master regulators, including transcription factors and microRNA. Both the RAG recombinase and activation-induced deaminase (AID) introduce characteristic rearrangements at antigen receptor loci, as well as off-target damage at oncogenes and tumor suppressor genes that contribute to lymphoid transformation. 18,19 Thus, lymph...

Pre-malignant lymphoid cells arise from hematopoietic stem/progenitor cells in chronic lymphocytic leukemia

“…The involvement of HSCs in the pathogenesis of mature lymphoid malignancies has been demonstrated by functional and genetic analysis [28,[30][31][32][33]. HSCs from the patients with mature lymphoid malignancies harbored identical somatic mutations that were detected in the tumor cells, indicating that early oncogenic events could target self-renewing HSCs during the stepwise disease developmental process.…”

“…However, we have reported that in mature lymphoid malignancies, such as chronic lymphocytic leukemia (CLL), the cellular propensity for clonal B cell development has been achieved at the HSC level [28,29]. It has also been reported that the genetic alterations specific for T cell lymphoma [30,31], follicular lymphoma (FL) [32], and hairy cell leukemia (HCl) [33] could be traced up to the HSC stage. These studies have suggested that even in relatively mature lymphoid malignancies, human HSCs could be a reservoir for genetic mutations, which constitutes a prime source for leukemia/lymphoma development.…”

Central Nervous System Lymphoma Newly Developed 12 Years after Remission of an Ocular Adnexal Lymphoma

“…Recently, accumulating evidence has shown that somatic alterations in uncommitted hematopoietic progenitors contribute to lymphomagenesis in some mature lymphoid malignancies [11]. It is plausible that at the stage before genetic rearrangement of antigen receptor loci those progenitors serve as reservoirs for further clonal evolution and contribute to the development of a second lymphoma.…”

High-throughput sequencing for noninvasive disease detection in hematologic malignancies

“…Additional recurrent driver mutations have recently been described and are thought to represent early initiating events required for malignant transformation. [113][114][115] Yet, these events have not been identified before overt malignancy; therefore, their role in detecting premalignant states is unclear.…”