Integrin Alpha M Chain Expression at Diagnosis Is Inversely Correlated with Cytoreduction Rate and Is Consistently Up-Regulated during Therapy in Acute Lymphoblastic Leukemia (ALL)

In childhood ALL, detection and quantification of minimal residual disease (MRD) is of crucial prognostic significance. Gene expression pattern of MRD cells undergoes treatment-related changes which provide insights into the mechanisms of therapy response and resistance. Our recent genome-wide analysis of blasts isolated from peripheral blood (PB) of pediatric patients with B-cell precursor (BCP-) ALL at early stages of induction therapy (day 8) revealed an up-regulation of the gene encoding for integrin alpha M chain (ITGAM, CD11b), and pointed to the involvement of adhesion receptors in the therapy response. In the present study we investigate expression of CD11b at protein level and its clinical relevance in BCP-ALL. At diagnosis, ALL cells heterogeneously express CD11b both in PB (mean 1839+/−515 MESF, 160 pts) and in bone marrow (BM) (655+/−114 MESF, 79 pts). At day 8, increased expression of CD11b has been observed in the majority of PB samples (77 of 100 pts, up-regulation range 1.5- to 74-fold, mean 8.2-fold). In BM, the CD11b expression has been consistently up-regulated at the clinically significant MRD timepoints of induction therapy (days 15, 33 and 78; ALL-BFM 2000 protocol). Moreover, since normal CD19+/CD10+ precursor cells are CD11b negative, the detection of CD11b improved discrimination of normal and leukemic blasts in the MRD positive cases with regenerating BM at day 78. Of particular interest, evaluation of the CD11b expression at diagnosis in context of the early therapy response disclosed its potential clinical relevance. In the bivariate data analysis, expression of CD11b significantly correlated with the blast reduction rate (BRR) and blast count (BC) in PB at day 8 (p=0.007 and 0.001, 103 pts). Similarly, the CD11b expression in BM significantly correlated with the BRR and BC in BM at day 15 (p=0.024 and 0.012, 58 pts). In the multivariate regression analysis, excluding BCR-ABL and MLL-AF4 positive ALL cases and using the additional clinical parameters at diagnosis (age, white blood cell count in PB, DNA index), CD11b expression at diagnosis was the most significant variable contributing to BRR at day 8 (p<0.001, standardized beta coefficient 0.61; 98 pts) and to BRR at day 15 (p<0.001, standardized beta coefficient 0.68; 47 pts). Taken together, our data indicate that the expression of CD11b contributes to the early therapy response and has a promising potential as an MRDspecific marker in BCP-ALL.