Infectious origins of childhood leukemia
نویسندگان
چکیده
Pediatric pre-B acute lymphoblastic leukemia (ALL) may develop from prenatal chromosomal translocations acquired in utero. For instance, the ETV6-RUNX1 gene rearrangement that occurs in ~25% of childhood ALL clones is found in the umbilical cord blood and Guthrie blood spots of 1 in 100 healthy newborns [1]. Despite a high frequency of occurrence of ETV6-RUNX1 in healthy neonates, only 1 in 14,000 carriers develop overt leukemia [2]. Other examples of pre-natally acquired lesions that are also found in healthy newborns include MLLand BCRABL1 gene rearrangements [1]. Studies on identical twins carrying pre-natal genetic lesions revealed significant differences in latency of leukemia development [1,3]. These observations corroborated that a prolonged clonal evolution process precedes overt leukemogenesis in ETV6-RUNX1 carriers [3]. However, until recently, the molecular mechanisms accelerating this clonal evolution remained unclear. Clonal evolution processes enable pre-leukemic pre-B cells to acquire secondary mutations that in some cases confer a competitive survival advantage over other pre-B cell clones. Pre-leukemic clones can, therefore accumulate in the bone marrow and acquire additional lesions that will ultimately give rise to overt leukemia. A recent study showed the clustering of mutation hot spots in B cells to regions frequently targeted by the enzymes Activation Induced Cytidine Deaminase (AID) and Recombination Activation Genes 1 and 2 (RAG1RAG2) [4]. Interestingly, AID and RAG1-RAG2 are genetic modifiers of the immunoglobulin (Ig) genes that are naturally expressed during B-lymphopoiesis. Although AID and RAG1/RAG2 are thought to be segregated to early (RAG1/RAG2) and late (AID) stages of B cell development, respectively, others and we recently showed that the two enzymes could be concurrently expressed during early B-lymphopoiesis. Our experiments identified the early B cell subset that is particularly vulnerable to such concomitant expression of AID and RAG1-RAG2. Further investigations revealed that a decrease in the B cell responsiveness of this pre-B subset to the cytokine IL-7 Editorial
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عنوان ژورنال:
دوره 6 شماره
صفحات -
تاریخ انتشار 2015