Acute myeloid leukemia bearing t(7;11)(p15;p15) is a distinct cytogenetic entity with poor outcome and a distinct mutation profile: comparative analysis of 493 adult patients

Abstract

Acute myeloid leukemia bearing t(7;11)(p15;p15) is a distinct cytogenetic entity with poor outcome and a distinct mutation profile: comparative analysis of 493 adult patients Acute myeloid leukemia (AML) with t(7;11)(p15;p15), which results in a NUP98-HOXA9 fusion, is a distinct entity, but this subtype has not been characterized in detail. In a comprehensive study comparing 11 such patients with another 482 adult patients, we found that those with t(7;11) were younger (P ¼ 0.0076) and female (P ¼ 0.0111), with almost all having the M2-subtype of AML (Po0.0001). Even when those with low-risk karyotypes were excluded, patients with t(7;11) had poorer overall survival than the other AML group (median 13.5 and 20 months, respectively, P ¼ 0.045) and poorer relapse-free survival (median 6 and 12 months, respectively, P ¼ 0.003). The NUP98-HOXA9 fusion was strongly associated with KRAS and WT1 mutations (P ¼ 0.015 and P ¼ 0.0018, respectively). We characterized four varieties of this fusion, among which NUP98 exon 12/HOXA9 exon 1b was present in all 11 patients. We developed a highly sensitive and specific assay to quantify the abundance of leukemic cells, and found that the fusion remained detectable in morphological complete remission, even after allogeneic stem cell transplantation, suggesting that this disease was highly refractory to very intensive treatment. AML with NUP98-HOXA9 fusion therefore appears to have a distinct clinical and biological profile, and should be regarded as a poor prognostic group.

NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights

“…29 The largest series identified 11 patients with NUP98-HOXA9 fusions among 493 consecutive AML cases in a Taiwanese population, for a frequency of 2.2%. 30 There have been suggestions that NUP98-HOXA9 fusions are more common in Asian countries than Western countries, because Asian patients have been overrepresented in published series and case reports of NUP98-HOXA9 fusions. 29,30 A study by the Groupe Francophone de Cytogenetique Hematologique demonstrated that 35% (23/66) of patients with hematopoietic malignancy and an 11p15 abnormality had a NUP98 translocation.…”

“…40,41 In addition, AML patients with a NUP98-HOXA9 fusion have worse overall survival and relapse-free survival. 30 Therefore, although the patient numbers are small, NUP98 fusions seem to be associated with poor-prognosis AML. …”

Outcomes after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia harboring t(7;11)(p15;p15)

“…While its actual prognostic relevance remains unclear, extremely high incidences of relapse in patients with t(7;11)(p15;p15) have been reported. [2][3][4][5] Although the cumulative incidence of relapse in the t(7;11)(p15;p15) group was significantly higher than that in the intermediate-risk group, there were no significant differences in survival between the two groups. Although these results suggest that allogeneic HSCT might overcome or at least ameliorate the poor prognosis of AML with t(7;11)(p15;p15), the present study is retrospective, and further prospective studies comparing allogeneic HSCT and chemotherapies are warranted to determine the prognostic relevance of AML harboring t(7;11)(p15;p15).…”

“…Kaito Harada, 1,2 Noriko Doki, 1 Jun Aoki, 3 Jinichi Mori, 4 Shinichiro Machida, 2 Masayoshi Masuko, 5 Naoyuki Uchida, 6 Yuho Najima, 1 Takahiro Fukuda, 7 Heiwa Kanamori, 3 Hiroyasu Ogawa, 8 Shuichi Ota, 9 Kazuei Ogawa, 10 Satoshi Takahashi, 11 Masanobu Kasai, 12 Akio Maeda, 13 Koji Nagafuji, 14 Toshiro Kawakita, 15 Tatsuo Ichinohe 16 and Yoshiko Atsuta…”

Analysis of the Hox epigenetic code

“…As the investigation on Hox genes unravels, more translation to clinical application is expected. Hox genes have been used as biomarkers such as HoxA9 [84] , MLL translocation [85] and NUP98 fusions [86] in leukemias. In breast cancer, other groups have investigated the developed of a two-gene test using qRT-PCR to determine the ration of HoxB13 expression to IL17RB expression that leads to predict the tumor recurrence in patients with eR-postive tumors taking tamoxifen [87,88] .…”