Myeloid leukemias and acute lymphoblastic leukemia (ALL).

Chronic eosinophilic leukemia (one case), acute myeloblastic leukemia with maturation (FAB type M2) (one case), acute myeloblastic leukemia with minimal differentiation (FAB type M0) (one case), and B-lineage acute lymphoblastic leukemia (three cases).

A chronic eosinophilic leukemia was diagnosed in a 82-year old female patient with a previous history of breast and pancreatic carcinomas (Forghieri et al., 2011). A M2-AML was diagnosed in a 52-yr old female patient. The patient died 5 months after the onset of the leukaemia (Eguchi et al., 1999). A M0-AML was found in a 55-yr old male patient who died after a short period of supportive care (Kralik et al., 2011). Three cases of B-cell ALL were diagnosed. There was an adolescent boy and a 26-yr old male patient (Roberts et al., 2014; Gu et al., 2016; Reshmi et al., 2017).

There was a monosomy 7 in two of the three documented cases (Forghieri et al., 2011; Kralik et al., 2011), and a trisomy 8 in 2 cases as well (Eguchi et al., 1999; Forghieri et al., 2011). The lymphoid cases were not documented.

In most cases, ETV6 exon 5 was fused to NTRK3 exon 15 (Forghieri et al., 2011; Roberts et al., 2014). In one case ETV6 exon 4 was fused to NTRK3 exon 15 (Eguchi: et al., 1999), and in another case, fusion transcripts contain ETV6 exons 1 through 5 fused to NTRK3 exons 13b and 14b or NTRK3 exons 13 through 18 (Kralik et al., 2011).
In solid tumors, ETV6 exon 5 - NTRK3 exon 15 fusion is the most frequent:
The fusion was exon 4 - exon 14 in most papillary thyroid carcinoma ceases, but one exon 5 - exon 14 fusion case (Leeman-Neill et al., 2014), and exon 5 - exon 15 in: secretory ductal breast carcinoma (Tognon et al., 2002), congenital mesoblastic nephroma (Knezevich et al., 1998; Rubin et al., 1998; Argani et al., 2000; Ramachandran et al., 2001; Watanabe et al., 2002; Henno et al., 2003; Anderson et al., 2006; Bayindir et al., 2009), secretory carcinoma of salivary glands (mammary analogue) (Skálová et al., 2010; Skálová et al., 2014), atypical Spitz tumors (Yeh et al., 2016), and also in a case of colon adenocarcinoma (Seshagiri et al., 2012). The classical exon 5 - exon 15 fusion is also found in congenital/infantile fibrosarcoma (Knezevich et al., 1998; Rubin et al., 1998; Bourgeois et al., 2000; Punnett et al., 2000; Argani et al., 2001; Dubus et al., 2001; Sheng et al., 2001; Miura et al., 2002; McCahon et al., 2003; Ramphal et al., 2003; Nonaka and Sun, 2004; Himori et al., 2005), but, also, a fusion NTRK3 exon 14 - ETV6 exon 6 was found in one case (Dubus et al., 2001).

The SAM-PNT (sterile alpha motif- pointed) domain of ETV6 is fused to the PTK (Protein Tyrosine Kinase domain) of NTRK3.

It leads to dimerization, and induction of CCND1 (cyclin D1) and increased cell cycle progression. ETV6/NTRK3 also leads to constitutive activation of the PI3K/AKT, RAS/RAF/MAPK, and PLCG pathways (Lannon and Sorensen, 2005).

ETV6/NTRK3

The t(12;15)(p13;q25) ETV6/NTRK3 is also found in: Secretory ductal breast carcinoma; Congenital mesoblastic nephroma; Congenital/infantile fibrosarcoma; Papillary thyroid carcinoma (PTC), especially so in radiation-associated PTCs; ALK-negative inflammatory myofibroblastic sarcoma; Secretory carcinoma of salivary glands (mammary analogue); atypical Spitz tumors, and rare other conditions.