Clinical and Biological Characterization of Adult Patients with Acute Myeloid Leukemia Bearing T(7;11)(p15;p15)—Analysis of 536 Patients
Authors: Chou Wen-Chien , Chen Chien-Yuan , Hou Hsin-An , Lin Liang-In , Tang Jih-Luh , Yao Ming , Tsay Woei , Ko Bor-Shen , Huang Shan-Yi , Tien Hwei-Fang 
Published: April 2020

Abstract
Purpose: Acute myeloid leukemia (AML) with t(7;11)(p15;p15), which results in fusion of NUP98 and HOXA9 genes, is rarely seen, especially in Western countries. Till now only few studies about this entity have been reported in literature, and they usually contained limited number of patients and did not have detailed characterization. This study evaluated the clinical and biological features of this group of patients from a large cohort.
Methods: From 1994 to 2007, we had comprehensive studies on a total of 536 AML patients. We compared the clinical features and genetic mutations of NPM1, FLT3/ITD, FLT3/TKD, AML1, K-RAS, N-RAS, CEBPA, MLL/PTD, JAK2, PTPN11, and WT1 between patients with and without this translocation. We also characterized the fusion points in patients with this chromosomal abnormality and devised a quantitative real-time PCR to specifically quantify the leukemia cells bearing the genetic fusion.
Results: Among the 536 patients, 11 patients (2%) were found to have t(7;11)(p15;p15). Comparing with the others, we found that AML patients bearing this translocation were younger (p=0.044), female predominant (p=0.010), and having a trend of higher lactate dehydrogenase (LDH) level (p=0.071). This group of patients had worse overall survival (OS) (median 13.5 vs. 36.5 month, p=0.005), relapse free survival (RFS) (median 6 vs. 15.5 months, p&lt;0.001), and disease free survival (DFS) (median 6 vs. 14.0 months, p=0.001) when compared with other AML patients. Even we excluded the patients with good risk karyotypes ((inv(16), t(15;17), and t(8;21)), patients with t(7;11) still presented with poorer OS, RFS, and DFS (median 13.5 vs. 21.0 months, p=0.030, 6 vs. 12.5 months, p&lt;0.001, and 6 vs. 11.5 months, p=0.008, respectively) than other patients. Multivariate analysis indicated this translocation was an independent factor for poor prognosis. Genetic analysis revealed that this translocation had strong association with K-Ras and WT1 mutations (p=0.013 and p=0.002, respectively). We analyzed the translocation breakpoints from those patients and found that there were 4 types of fusion, namely NUP98 exon 11/HOXA9 exon 1b, NUP98 exon 11/HOXA9 exon 2, NUP98 exon 12/HOXA9 exon 1b, and NUP98 exon 12/HOXA9 exon2. Among these types of fusion, NUP98 exon 12/HOXA9 exon 1b was obviously present in all the analyzed patients, while other types of fusion were seen in only some of them. Our real-time PCR could sensitively detect 10 copies of plasmids in a background of complex cDNA extracted from cells without this chromosomal abnormality, and specifically quantify the fusion transcripts from patients’ leukemia cells which were serially diluted up to 10,000 fold by those without this genetic abnormality. When applying this assay in 4 patients’ bone marrow cells along their treatment courses, we found that the signals largely remained detectable, even after allogeneic hematopoietic stem cell transplantation. This phenomenon coincided with the fact that this disease was highly refractory to even the most intensive treatment currently available.
Conclusion: AML with NUP98-HOXA9 fusion has a characteristic profile in both clinical and biological aspects, and should be regarded as a poor prognostic group.