Impact of IRF4/MUM1 Expression on Adult T-Cell Leukemia/Lymphoma and Treatment Outcome

Introduction:

HTLV-1 related adult T-cell leukemia-lymphoma (ATLL) remains fatal, thus urging development of new therapies. Interferon regulatory factor 4 (IRF4), also known as MUM1, is a transcription factor expressed in various aggressive B-cell and T-cell lymphomas (1). IRF4 has been reported to be highly expressed in HTLV-1 transformed cells and in aggressive leukemic forms of ATLL, and has also been implicated in interferon resistance. However, IFR-4/MUM1 expression, and its pathogenic role in ATLL have not been fully investigated. We previously reported lack of IRF4/MUM1 in leukemic ATLL specimens from patients who responded to AZT-interferon-alpha (AI). In this study, we characterized the expression of IRF4/MUM1 in our expanded ATLL cohort.

Methods:

ATLL specimens from 73 chemotherapy naïve patients of all subtypes [lymphomatous (L) n=31, acute (A) n=36, unfavorable chronic (UC) n=5, and smoldering (S) n=1] were analyzed for MUM1 expression. Cases were analyzed or confirmed by immunohistochemistry at our institution using anti-human MUM1 antibody (Dako) on formalin-fixed paraffin-embedded tissue or cellblock sections prepared from cytospun CD4+-enriched leukemic samples. The cutoff positive value for MUM1 expression was 30%. MUM1 expression was correlated with treatment outcome.

Results:

In 73 patients the proportion of MUM1+ cases was as follows: L (28/31 =90%), A (7/36 =19%), UC (1/5 =20%), and S (0/1 =0%) (Figure 1A). MUM1 expression was analyzed in 33 chemotherapy naïve patients with A (n= 28) or UC type (n=5) treated with AI; only 3 patients (A n=2, and UC n=1) were MUM1+ and had partial response (PR) (UC n=1), stable disease (SD) (A n=1), and no response (NR) (A n=1) respectively (Figure 1B). All 9 patients who achieved a complete response (CR) (A n=7, and UC n=2) and 6 patients with PR (A n=5, UC n=1) were MUM1-. The cumulative 3-year overall survival (OS) rates in MUM1- (n=37) vs. MUM1+ (n=36) patients were 23% vs. 10% respectively (p=0.68) (Figure 2). Notably, the great majority of patients in the MUM1- group (33/37=89%) were treated with AI as first line therapy and were A-type (27/37=73%), while most patients in the MUM1+ group (26/36=70%) were treated with chemotherapy upfront and were L-type (23/36=64%). The cumulative 3-yr progression-free survival in MUM1- patients treated with AI was 28% as compared to 0% in MUM-1+ treated with chemotherapy (Figure 3).

Conclusion:

Our results demonstrate that MUM1 expression is highly associated with L-type ATLL. Patients with aggressive leukemic ATLL subtypes treated with AI generally lacked MUM1 and had a significant better outcome than L-type patients treated with chemotherapy. This study suggests that MUM1 expression may influence the biology at ATLL subtypes and response to interferon-based therapy. Targeting IFR-4/MUM1 function in L-type ATLL should be considered as a therapeutic strategy. The analysis of additional cases is still ongoing and the final results will be presented at the meeting.

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