A novel subgroup of B-cell ALL with CD2 expression that does not belong in the other defined groups has been recently discovered26,27. This subgroup harbors intragenic deletions in the ERG gene that codes veins-665093_640for a transcription factor in hematopoiesis. It has not been observed in T-cell ALL and thus appears unique to B-cells. Being microscopic, it escapes cytogenetic detection, and hence molecular diagnosis by PCR, MLPA or deep sequencing for copy number variants would be necessary for its diagnosis. PCR may be preferred because of the low number of recurrent deletions and the high sensitivity of the method, while MLPA may be more readily available.

Among B-ALL patients, ΔERG occur in about 5%, with reports of 3-7% prevalence in the pediatric population26,27. By itself, ΔERG confers significantly favourable prognosis in terms of low relapse risk, and high event-free survival (HR of 0.2 to 0.4)26,27 and overall survival. Outcome on standard-risk regimens have been extremely positive stressing its role as a prognostic marker in B-cell ALL. Surprisingly, a high frequency of high-risk IKZF1 deletions occurs in patients with ERG deletions. However, the latter seems to impose its favourable prognosis and risk despite the presence of IKZF1 deletions (HR of 0.3). Thus ERG deletions are a very useful clinical marker in B-ALL patients. As the two landmark studies on ΔERG have focused on pediatric patients, their clinical significance in adults needs study.

ERG deletion may be a secondary mutation and not the driver mutation of leukemogenesis as shown by loss of deletion during relapse in some patients26. This change in behavior might also make it an unpredictable MRD marker for early detection of relapse. Recently patients with ERG-deletions have been shown to overexpress DUX4 and harbor DUX4-IGH fusion transcript28,29. However, their cooperative or coincidental finding needs further study in terms of both mechanism as well as causation.

References

  1. Zaliova M, Zimmermannova O, Dörge P, et al. ERG deletion is associated with CD2 and attenuates the negative impact of IKZF1 deletion in childhood acute lymphoblastic leukemia. Leukemia. 2014;28(1):182-185. doi:10.1038/leu.2013.282.
  2. Clappier E, Auclerc MF, Rapion J, et al. An intragenic ERG deletion is a marker of an oncogenic subtype of B-cell precursor acute lymphoblastic leukemia with a favorable outcome despite frequent IKZF1 deletions. Leukemia. 2014;28(1):70-77. doi:10.1038/leu.2013.277.
  3. Yasuda T, Tsuzuki S, Kawazu M, et al. Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults. Nat Genet. 2016:1-8. doi:10.1038/ng.3535.
  4. Liu Y-F, Wang B-Y, Zhang W-N, et al. Genomic Profiling of Adult and Pediatric B-cell Acute Lymphoblastic Leukemia. EBioMedicine. 2016;8:173-183. doi:10.1016/j.ebiom.2016.04.038.