JAM-C Expression as a Biomarker to Predict Outcome of Patients with Acute Myeloid Leukemia—Letter

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 (SSC^loCD45^dim) 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 (SSC^loCD45^dimCD33⁺CD34⁺CD38^dimCD123⁺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. 6342