Clinical and Laboratory Studies of 23 Patients with Acute Myeloid Leukemia Harboring t (7; 11) (p15; p15) Translocation

Introduction

Chromosomal translocations involving nucleoporin NUP98 protein have often been described in acute myeloid leukemia (AML). Fusing NUP98 gene at chromosome 11 into class I homeoprotein HOXA9 gene at chromosome 7 through chromosome translocation was detected more than fifteen years ago. Translocation t (7; 11) (p15; p 15) is a rare but recurrent chromosome aberration in AML, which was first reported in 1982 as an additional translocation in a patient with Philadelphia chromosome-positive chronic myeloid leukemia (CML). Subsequent studies have indicated that this translocation was also found in de novo AML, CML and myelodysplastic syndrome (MDS). In this study, we retrospectively investigated the clinical and laboratory profile of this aberration.

Methods:

From August 1997 to July 2015, twenty-three (0.76%) of the approximately 3000 newly diagnosed patients with de novo AML at our hospital were found to have the chromosome translocation t (7;11) (p15;p15). The diagnosis was based on bone marrow cell morphology, cytochemistry, immunophenotyping and chromosomal analysis.

Karyotypes of the 23 patients were analysed with R-banding technique. Transcripts of NUP98-HOXA9 were amplified from 9 patients with PCR. The PCR products were resolved on and extracted from 1% agarose gels and sequenced. 

Results

Clinical and laboratory characteristics of patients with t (7;11)(p15;p15)

Of the twenty-three patients with t (7;11)(p15;p15), fifteen were females and eight were males. The median age was 34 years, ranged from 18 to 67 years.  According to FAB morphology criteria, eleven were M2 subtype, one of whom complicated with myelofibrosis; six were M5,five were M4, and one was M6. The blast count in bone marrow aspiration ranged from 27% to 86%. All the 23 cases expressed myeloid-associated antigen CD33, 21 cases expressed CD117 and CD13, HLA-DR and CD34 were expressed in 17 patients. None of the patients expressed lymphoid-associated antigens except two cases partially expressed CD9. Clonal chromosomal abnormalities of all the patients were t(7;11) (p15;p15). Additional trisomy 8 was found in only one patient. FLT3/ITD was positive in two of twenty-one patients. 

Outcome

All the twenty-three patients received conventional induction chemotherapy including anthracyclines, cytarabine and homoharringtonine. The complete remission (CR) rate was 86.9% (20/23); the median follow up was 16 months; and the median disease-free survival and the median overall survival were 12 (0-45) months and 16 (2-50) months, respectively. Nine patients were still alive till last follow-up, one patient was lost for followed up and the other thirteen patients died. Among the nine survivals, four underwent sibling donor stem cell transplantation during CR1 period and two patients underwent Haplo-HSCT, unrelated donor allogeneic transplant for the seventh one, and the left two had shorter CR1 period because they were newly diagnosed. Among the thirteen dead patients, three did not achieve a complete remission and died during induction chemotherapy; one relapsed twice after underwent sibling donor stem cell transplantation three times and then died of acute graft-versus-host disease and gastrointestinal infection; one underwent sibling donor stem cell transplantation during CR1 period and then died of graft-versus-host disease and the other eight patients died after intensive chemotherapy including high-dose Ara-C, among whom, one with FLT3/ITD positive achieved CR1 for 8 months, and one died during treatment at the 29^th month after relapsed twice at the 21^th and the 27^thmonths, respectively.

Two types of fusion break points in NUP98-HOXA9

Four types of fusion transcripts have been previous reported as the consequence of alternative splicing.However, in our study, we only identified type I and type III fusion by sequencing. Type I included NUP98 ex.12 and HOXA9 ex.1b and type III included NUP98ex.11 and HOXA9 ex.1b.

Conclusions

Acute myeloid leukemia with t (7;11)(p15;p15) is a rare and distinct disease. Most patients with this translocation are female at younger age and have special clinical and hematological characteristics such as M2-subtype of AML, easy to relapse and poor prognosis. There are no target chemotherapy drugs to improve the prognosis so far.  And whether stem cell transplantation is the therapeutic way for the disease need to be further investigated.