-

-

-

-

61 yrs

M

-

-

-

-

5.4

6.8

56

22% myeloblasts

60% cellularity; 30% intermediate-to-large size blasts with open chromatin and no Auer rods; decreased trilineage hematopoiesis; significant dysplasia of erythroid elements.

Bone marrow and peripheral blood smear findings were both morphologically consistent with acute myeloid leukemia (AML).

Flow cytometry of the bone marrow sample showed a myeloblast population representing 33% of the cells that were positive for CD34, CD33, CD117, CD11b, CD11c, CD13, and cytoplasmic MPO.

No.

not performed

Acute Myeloid Leukemia, NOS (WHO, 2016).

12-2017

The patient began induction chemotherapy regimen on 1/7/2018 consisting of 7 days of daily cytarabine infusion and 3 days of daily daunorubicin. On 2/15/2018 he was treated for refractory AML with a five-day course of mitoxantrone, etoposide, and cytarabine.

-

-

Remission never achieved.

A

03-2018

3 +

Bone marrow aspirate.

24

GTG band level: 350-400

47,XY,t(12;13)(p13;q12),+21 [20]

Karyotype following completion of induction chemotherapy 2/7/2018; 46,XY,t(12;13)(p13;q12)[3]/47,XY,t(12;13)(p13;q12),+21[8]/47,XY,+8,t(12;13)(p13;q12)[4]/ 48,XY,+8, t(12;13)(p13;q12),+21[5] [Figure 1]

Fluorescence in situ hybridization (FISH) using ETV6 LSI break apart probe (Abbott Molecular, Des Plaines, IL USA).

Fluorescence in situ hybridization (FISH) with EVT6 probe revealed one fusion signal and split signal corresponding to the t(12;13)(p13;q12) however, the partner gene on chromosome 13q12 was not tested [Figures 2].

Next generation sequencing (NGS) using a myeloid 54-gene panel.

A nonsense variant (.c.2693G>A) in the ASXL1 gene was detected using the Illumina TruSight Myeloid Panel: Nonsense variants in ASXL1 gene are associated with poor prognosis (Metzeler et al, 2011).

The t(12;13)(p13;q12) is very rare in hematological malignancies with only 14 cases including the present case have been reported [Table 1]. Six cases were diagnosed with myeloproliferative neoplasms with eosinophilia (MPNeo), five had AML, and the remaining three were pediatric ALL [see Table1 for references]. Molecular characterization of the t(12;13) breakpoints revealed the rearrangement of ETV6/12p13 gene in 9/14 cases. On the other hand, FLT3 gene was implicated as the involved partner gene on chromosome 13 in five cases. All five were diagnosed with MPNeo, nevertheless the disease was rapidly fatal in three patients [Table 1]. FTL3 encodes a member of the receptor tyrosine kinase subclass III family of receptors, which is expressed in early hematopoietic progenitor cells (Gilliland & Griffin, 2002; Stirewalt & Radich 2003). Mutations in FTL3 gene are found in approximately 30% of AML cases, yet this gene is rarely involved in translocations. Vu et al reported the first case of t(12;13)(p13;q12) in MPNeo, with the translocation resulting in the creation of an ETV6-FLT3 fusion gene. Reciprocal ETV6/FLT3 and FLT3/ETV6 transcripts were detected by RT-PCR; however, at the protein level, only ETV6/FLT3 was expressed in the patient's leukemic cells (Vu et al, 2006). The putative oncogenic function gained as a result of the ETV6-FLT3 fusion is the constitutive activation of the tyrosine kinase domains of FLT3. One case of t(12;13)(p13;q12)-related AML involving a ETV6-CDX2 fusion has been described as well (Chase et al, 1999). Although FISH results in the present case revealed the involvement of ETV6 gene in the t(12;13) translocation, it is unknown whether a specific gene may have been affect at the 13q12 locus.Unlike FLT3 gene, ETV6/12p13 translocations is commonly detected in a wide spectrum of hematological malignancies lymphoid and myeloid; with at least 48 chromosomal bands and 30 ETV6 partner genes have been reported. The chimeric oncoprotein resulted from the t(12;13) may have a therapeutic implications. Although the ETV6-FLT3 positive leukemia has shown some sensitivity to FLT3 inhibitors, more cases are needed to appreciate the response.Table 1; Clinical data on patients reported with t(12;13)(p13;q12)

Case #	Age/Sex	Diagnosis	Genes involved	Clinical Status	Survival (months)	Reference
1	68Y/F	MPN-eo	ETV6-FLT3	Deceased	21	Vu et al.,  2006
2	40Y/F	MPN-eo	ETV6-FLT3	Alive - CR	11	Falchi et al.,  2014
3	60Y/M	MPN-eo	ETV6-FLT3	Deceased	7	Walz et al.,  2011
4	49Y/M	MPN-eo	NR	Deceased	11	Chiyoda et al.,  1994
5	29Y/M	MPN-eo	ETV6-FLT3	Deceased	13	Walz et al., 2011
6	33Y/M	T-ALL and MPN-eo	ETV6-FLT3	Alive - CR	72	Chonabayashi, et al., 2013
7	5Y/M	ALL	NR	Alive - CR	24	Keene, 1987
8	9Y	ALL	NR	Alive - CR	NR	Heerema et al., 2000
9	17Y/F	ALL	ETV6-?	Deceased	29	Wlodarska et al., 1987
10	62Y/F	MDS-RAEB	NR	NR	NR	Knapp et al., 1985
11	51Y/M	AML-M0	ETV6-?	NR	NR	Tosi et al., 1998
12	40Y/M	Therapy-related AML	NR	Deceased	1	Clavio et al., 2001
13	66Y/M	AML	ETV6-CDX2	Deceased	40	Chase, 1999
14	61Y/M	AML	ETV6-?	Alive	3	Present case 2018

ALL: F; female: M; male; acute lymphoblastic leukemia; AML: acute myeloid leukemia; CR: complete remission; MDS-RAEB: myelodysplastic syndrome with refractory anemia and excess blasts; MPN-eo: myeloproliferative neoplasms with eosinophilia; NR: not reported; PTCL: peripheral T-cell lymphoma; Y: years.