The Prognostic Role of Jagged-1 Protein Expression In Acute Myeloid Leukemia Patients

Jagged-1 is a member of the Delta/Serrate/Lag-2 (DSL) family of proteins that are ligands for Notch receptors. Aberrant Jagged-1/Notch-1 signaling is posited to promote the development of AML by inducing excessive self-renewal with a concomitant block in cell differentiation. Moreover, Notch-1 signaling has been identified as a critical factor involved in the maintenance of a pool of self-renewing hematopoietic stem cells (HSC) as well as AML stem cells. So far there were no reports on the clinical role of Notch-1 and Jagged-1 expression in AML.

In this study we evaluated the expression of Jagged-1 and Notch-1 proteins in AML blasts and CD34+ peripheral blood stem cells (PBSC) collected during mobilization procedures before autologous stem cell transplantation. In addition, in AML patients we correlated the expression of both proteins with known prognostic factors and response to treatment.

The expression of Notch-1 and Jagged-1 proteins was examined in leukemic blasts isolated from bone marrow or peripheral blood of 53 de novo AML patients with median age 57 years (range 21–82). CD34+ collected from 13 lymphoma patients (11 multiple myeloma, 1 Hodgkin lymphoma, 1 non-Hodgkin lymphoma) with median age 57 (range 21–69 years) served as a control. All measurements were carried out using multi-colour flow cytometry. In parallel, the isotype controls were performed for all measurements. Protein expression was assessed as a percentage of Notch-1 and Jagged-1 positive cells. The cut-off 20% was used to subdivide patients into “low-expressers” and “high-expressers” group.

We found that the median expression of Jagged-1 was significantly higher in AML blasts (18,2%; range 0,9–62,4%) as compared to CD34+ PBSC (3,0%; range 0,9–21%); p<0.0001. In contrast, the expression of Notch-1 in AML patients (median 1,4%; range 0,1–24,8%) was lower than in the control CD34+ cells (median 3,85%; range 0,7–16%); p<0.004. There was no correlation between Jagged-1 and Notch-1 protein expression in both AML blasts and PBSC.

Jagged-1 expression was significantly higher in AML patients with WBC ≤20G/L (median 21,2%) compared to group with WBC >20 G/L (median 9,85%); p<0.004. Consequently, we found the significant negative correlation between Jagged-1 expression and WBC count (p<0.02). Patients with good-risk karyotype according to SWOG classification showed significantly higher expression of Jagged-1 protein as compared to intermediate and poor risk group (medians 21,8% vs. 11,5% respectively; p< 0.02).

Thirty two out of 53 AML patients received standard induction chemotherapy with daunorubicine and cytarabine (“3+7”), 21/53 received non-intensive therapy. Nineteen (61%) of intensively treated patients achieved complete remission (CR). We observed that the CR rate in “high-expressers” of Jagged-1 was significantly higher than in the “low-expressers” group (80% vs. 43% respectively; p=0.04). Additionally, a good karyotype and a high expression of Jagged-1 protein were the only factors associated with higher probability of CR (p=0.05, p<0.01, respectively) in univariate analysis.

There was no statistical association between the Notch-1 expression and response to treatment, karyotype or tumour size associated risk factors as: WBC, percentage of leukemic blasts in bone marrow and LDH. Moreover, no correlations between Notch-1 and CD34 expression as well as Notch-1 and differentiation markers (CD13, CD14, CD15, CD33) expressions in AML blasts were found.

Jagged-1 protein is highly expressed in AML blasts and correlates with better response to standard chemotherapy, favorable karyotype and lower WBC in AML patients. These data clearly demonstrate an important role of Jagged-1 in AML biology. A better understanding of autonomous Jadded-1 signaling in AML may create new options for therapeutic interventions in AML.

Robak:Johnson & Johnson: Research Funding.