February 2017 - Presented by Dr. Ruijun Su & Dr. Jeffrey Gregg


Yagasaki et al. identified an ETV6-ACSL6 chimeric gene in three patients with t(5;12)(q31;p13), including refractory anemia with excess blasts (RAEB) with basophilia, AML and AEL [4]. Different fusion genes were identified by cytogenetic and FISH analysis in these patients: a short in-frame fusion of exon 1 of ETV6 to the 3’UTR of ACSL6, an out-of-frame fusion of exon 2 of ETV6 to exon 11 of ACSL6, and an out-of-frame fusion of exon 1 of ETV6 to exon 1 of ACSL6 [4]. FISH with bacterial artificial chromosomes (BACs) specific probes for the ETV6 and ACSL6 genes were performed on two patients with t(5;12)(q31;p13)-associated PV and demonstrated the involvement of ETV6 and the 5’ region of the ACSL6 in the translocation [7]. In the current case, FISH for t(5;12)(q31;p13) was negative, most likely due to PDGFRB (5p33.1) being many kb distal (toward the telomere end) to ACSL6 (5q31). Therefore, detection of the rearrangement was missed by this probe. RNA-seq showed the current rearrangement resulted in an out-of-frame fusion of ETV6 exon 1 and ACSL6 exons 2-21. This particular rearrangement to our knowledge is novel and has not been previously reported. Similar rearrangements involving out-of-frame fusions of ETV6 exon 1 to ACSL6 have been reported in the above five cases [4, 7]. These observations suggest that the disruption of ETV6 and ACSL6 may lead to the pathogenesis of hematological malignancies with t(5;12)(q31;p13).

Generation of out-of-frame fusions, as in ETV6-ACSL6, can lead to functional consequences. Molecular analysis of these fusion genes leads to multiple proposed mechanisms of leukemogenesis including loss of function of the fusion gene, affecting ETV6 and/or ACSL6 gene [4], and, loss of the untranslocated ETV6 and activation of a proto-oncogene in the vicinity of a chromosomal translocation [7]. An example is interleukin 3 (IL-3, which is located near the breakpoint at 5q31). When activated, IL3 promotes proliferation and differentiation of various hematopoietic cell lineages. Constitutive activation and dysregulated expression of IL3 lead to a marked cell proliferative state, which can explain the eosinophilia observed in the majority of cases with t(5;12)(q31;p13) [8, 9, 10], including the current case. The ETV6-ACSL6 rearrangement can be the driving mutation of leukemogenesis of CEL although detailed molecular mechanisms have not determined. Besides the ETV6-ACSL6 fusion, other genomic alterations were identified including BRIP1 (DNA repair/chromatin stability), NF1 (tumor suppressor gene), U2AF1 (RNA splicing) (Table 1, not shown). The findings further confirm that leukemia may develop as the consequence of an array of molecular alterations that disrupts many facets of hematopoietic precursor cell development to induce leukemia transformation. These processes may include the regulation of cell proliferation, differentiation, self-renewal, survival, cell cycle checkpoint control, DNA repair and chromatin stability, and cell dissemination.

In conclusion, we have reported a case of chronic eosinophilic leukemia, NOS, with a t(5;12)(q31;p13) resulting in a novel ETV6-ACSL6 gene fusion. Myeloid neoplasms with PDGFRA, PDGFRB or FGF1 abnormalities are the most important groups of diseases in the differential diagnosis of eosinophilia-associated myeloproliferative neoplasms, as some of these patients may be responsive to tyrosine kinase inhibitor (TKI) therapy. Our current report and the five cases published previously suggest that ETV6 plays a pivotal role in the regulation of myeloid hematopoiesis, especially at the eosinophilic progenitor level and therefore, these patients will not be responsive to TKI. Further molecular studies are needed to clarify the underlying mechanism of ACSL6 in leukemogenesis and how aberrant expression of a gene involved in fatty acid synthesis can result in clonal expansion.


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