A Novel Three-Way Translocation Involving <i>ETV6-IL3</i> Drives AML with Eosinophilia

Introduction Eosinophilia is seen in a wide range of disease processes, both reactive and clonal. In AML the presence of eosinophilia often represents underlying gene rearrangements involving CBFB, PDGFR, or ETV6. Identifying the underlying cytogenetic (CG) aberration is informative for prognostication and therapeutic decision-making. Inv(16) AML tends to be chemotherapy sensitive with high remission rates. PDGFR rearrangements may confer sensitivity to tyrosine kinase inhibitors (TKI). ETV6 rearrangements involving ABL1 may portend a chemotherapy resistant course. Here, we dissect the molecular mechanisms of an unusual case of AML involving a three-way translocation of ETV6, IL3, and RP11-815J21.3 [t(5;12;15)] that correlated with profound eosinophilia. Methods IL-3, IL-5, and IL-7 levels were measured by a multi-cytokine Luminex panel (Eve Technologies) in the patient's serial plasma and bone marrow (BM) aspirate samples, healthy donor, and non-eosinophilic AML samples. IL3 mRNA expression was assessed by qPCR. Eosinophils were purified using magnetic bead separation and the marker Siglec-8 and were then evaluated for t(5;12;15) by FISH. Clonal evolution was inferred from variant allele and FISH frequencies. Results A 48 year old male presented with fevers and WBC 243k/μL (77% blasts, no eosinophilia). BM biopsy confirmed AML with myelomonocytic differentiation. FISH/CG revealed a NUP98-NSD1 translocation in 91% of cells and NGS revealed FLT3ITD and RUNX1Q397fs*197 mutations. 7+3 and midostaurin were started and the day 21 BM showed residual disease. He was transitioned to azacitidine, venetoclax, and gilteritinib with subsequent remission, loss of FLT3ITD mutation, and undetectable NUP98-NSD1. 7 months after diagnosis he developed profound peripheral blood (PB) eosinophilia, reaching an absolute eosinophil count of 48.2k/μL. BM biopsy showed AML relapse with 19% eosinophils. The NUP98-NSD1 translocation and RUNX1 mutation were now detected, notably, with no FLT3ITD mutation but with a new subclonal three-way translocation, t(5;12;15), detected in 45% of cells, involving IL3, ETV6, and RP11-815J21.3 loci respectively. Over the next 4 months, peak eosinophilia in the BM (52%) corresponded to the highest abundance of t(5;12;15) (57% of cells). When this translocation was later reduced to 2.5% of cells by chemotherapy, the eosinophilia in the BM resolved. Variant allele frequencies suggest that this relapse was driven by the NUP98-NSD1; RUNX1; FLT3ITD mutant clone rather than the IL3-associated clone. At time of initial relapse with eosinophilia, PB plasma and BM aspirate IL-3 levels were significantly elevated (54 pg/mL, 123 pg/mL) compared to normal and non-eosinophilic AML samples (<0.3-1.3 pg/mL). At remission, when eosinophilia had resolved, IL-3 levels declined (8 pg/mL). IL-5, a regulator of eosinophil maturation, was persistently elevated (23-50 pg/mL vs 1-9 pg/mL in normal and other AML) but did not correlate with extent of eosinophilia. IL-7, not involved in eosinophil expansion, showed levels similar to those seen in other AML. Elevated IL3 mRNA expression by qPCR correlated with IL-3 protein levels and degree of PB eosinophilia. To test whether the eosinophils were derived from the mutant clone, eosinophils were purified. The ETV6-IL3 translocation was identified in 39% of these cells. Lastly, the percentage of PB eosinophils was greater than the percentage of interphase PB cells positive for ETV6-IL3 (71% Eos vs 32% FISH+). This suggests both autocrine and paracrine effects from IL-3. Interestingly, we also observed evolution of the AML blasts, possibly secondary to IL-3. At diagnosis, blasts were CD123- (IL-3 Receptor α) but became CD123+ at subsequent relapse, suggesting selection for response to IL-3 signaling. Conclusion Here, we describe a case of a translocation involving the IL3 locus, resulting in elevated IL-3 production with autocrine and paracrine induction of eosinophilia. IL-3 may have also promoted AML relapse and blast evolution. A similar mechanism of translocation induced enhancer proximity can be seen in IL3-IGH B-ALLs with eosinophilia. This ETV6 enhancer specific etiology is important to distinguish from the t(5;12)(q33;p13) PDGFRB-ETV6 rearrangement that induces eosinophilia, is cell intrinsic, and is TKI responsive. AML involving t(5;12;15)(q31;p13;q25) is not TKI responsive, rather more likely responds to chemotherapy.

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