JAM-C Expression as a Biomarker to Predict Outcome of Patients with Acute Myeloid Leukemia—Letter
Authors: Malte von Bonin, Katharina Moll, Michael Kramer, Uta Oelschlägel, Martin Wermke, Christoph Röllig, Christian Thiede, Gerhard Ehninger, Alwin Krämer, Carsten Müller-Tidow, Ioannis Mitroulis, Martin Bornhäuser
Journal: Cancer Research (2018)

Prognosis prediction in patients with acute myeloid leukemia (AML) mainly relies on patient-related factors (e.g., age) and the detection of genomic lesions (1). De Grandis and colleagues have published that junction adhesion molecule C (JAM-C) is expressed on leukemia-initiating cells (LIC), acts through SFK pathway activation, and independently predicts adverse outcome in a cohort of patients with CD34+ AML (2). The prognostic value was analyzed in the context of LIC because JAM-C has been described to regulate homing of stem cells to the hematopoietic niche (3).We measured JAM-C by flow cytometry on bulk leukemic cells (SSCloCD45dim) of bone marrow samples biobanked from a subset of patients treated within the randomized AML96 trial (NCT00180115; Table 1A; ref. 4). JAM-C expression showed a moderate, but statistically significant inverse correlation with CD34 expression (Table 1B) and was associated with the absence of double-mutated CEBPA (Table 1C). After having determined a 10% cutoff for JAM-C by cross-validation, CD34 and JAM-C could be shown to be both associated with a reduced probability to achieve a complete remission after induction therapy (CR1; Fig. 1A). Neither CD34 nor JAM-C were predictors of relapse-free survival (RFS; Table 2A). Using the same cutoff, JAM-C+ patients showed a significantly shortened median overall survival (OS; JAM-C+ 10.1 months vs. JAM-C− 26.7 months, log-rank P = 0.0062), whereas CD34 only conveyed a trend toward an impaired survival (Fig. 1B and C). Even in multivariate analysis, the prognostic value of JAM-C positivity remained statistically significant (Table 2B). When patients with biallelic-mutated CEBPA (n = 18) and with unknown CEBPA mutation status (n = 4) were excluded, JAM-C expression maintained its significant influence on OS and CR1 (data not shown).In contrast to de Grandis and colleagues, JAM-C positivity did not negatively impact RFS. Still, in our cohort, JAM-C positivity remained an independent predictor of worsened OS, which might be attributable to the reduced likelihood to achieve a CR1. Complementary to the observation published by de Grandis and colleagues, our data suggest that the association between JAM-C expression and reduced OS might not necessarily be linked to an association with the stem cell compartment and its accompanying niches, as we have detected JAM-C on the bulk of leukemic cells. However, we cannot exclude that the enhanced JAM-C expression on the bulk of leukemic cells was associated in parallel with an increase in LICs as defined by de Grandis and colleagues (SSCloCD45dimCD33+CD34+CD38dimCD123+JAM-C+), although we have even observed an inversed association between the expression of CD34 and JAM-C.Finally, our data further support the significance of JAM-C as a prognostic marker in patients with AML, even for CD34− cases and measured within routine flow cytometric AML diagnostics. Because of its expression on bulk leukemic cells, targeting JAM-C by immunotherapy as proposed by de Grandis and colleagues could not only help to mitigate LICs (with a crucial importance for the long-term prognosis) but could be also used to reduce tumor burden in the short run.See the Response, p. 6342No potential conflicts of interest were disclosed.We gratefully thank Triantafyllos Chavakis for helpful discussions.