Lack of CD24 antigen expression in B-lineage acute lymphoblastic leukemia is associated with intrinsic radiation resistance of primary clonogenic blasts

Abstract

The radiation sensitivity of primary clonogenic blasts from 27 children with immunologically classified CD2-CD5-CD7-CD19+slg- B-lineage acute lymphoblastic leukemia (ALL) was analyzed using leukemic progenitor cell (LPC) colony assays. Radiation survival curves of primary clonogenic blasts (ie, LPC) were constructed for each patient using computer programs for the single-hit multitarget as well as the linear quadratic models of cell survival. The D0 values ranged from 49 to 891 cGy (median, 239 cGy; mean +/- SE, 307 +/- 44 cGy) and the alpha values ranged from 0.000 to 2.047 Gy-1 (median, 0.156 Gy-1; mean +/- SE, 0.284 +/- 0.078 Gy-1). Patients were divided into groups according to sex, age, white blood cell count (WBC) at diagnosis, plating efficiency of primary bone marrow blasts, and immunophenotype. Patient sex, age, WBC at diagnosis, or in vitro plating efficiency was not associated with radiation resistance. Notably, freshly isolated primary clonogenic blasts from patients with a CD19+CD24-CD34+ composite immunophenotype (stage I B-cell precursor [BCP]) had 2.2-fold higher D0 values (P = .005) and 3.4-fold lower alpha values (P = .05) than those from patients with a CD19+CD24+CD34+ (stage II BCP) or CD19+CD24+CD34- (stage III BCP) immunophenotype. The relative values for CD24- primary clonogenic blasts signify greater intrinsic radiation resistance. Furthermore, the CD19+CD24-CD34+ immunophenotype had a larger radiation resistant fraction. Whereas only 60% of CD19+CD24+CD34+ and 33% of CD19+CD24+CD34- cases had clonogenic blasts with alpha < or = 0.2, 100% of CD19+CD24-CD34+ cases had clonogenic blasts with alpha < or = 0.2. Furthermore, clonogenic blasts from established CD19+CD24- B-lineage ALL cell lines were significantly more radiation resistant than CD19+CD24+ B-lineage ALL cell lines. Notably, radiation doses sufficient to induce apoptosis of CD24- B-lineage ALL cells were higher than those capable of inducing apoptosis in CD24+ B-lineage ALL cells. Thus, the lack of CD24 surface antigen expression in B-lineage ALL is associated with intrinsic radiation resistance at the level of primary clonogenic blasts.

Stromal niche communalities underscore the contribution of the matricellular protein SPARC to B-cell development and lymphoid malignancies

“…Indeed, the lack of CD24 in pre-B acute lymphoblastic leukemia has been associated with radiation resistance of primary clonogenic blasts. 38 Consistently, in our experiments in vivo, we found that the lymphoid populations that were expanded in p53 −/− and p53 −/− /Sparc −/− mice with splenic lymphomas, showed a decrease in CD24 expression when infiltrating the BM, which was more prominent in the p53 −/− /Sparc −/− setting constintently with the enhanced micro-environmental expression of the ligand P-selectin. Through the modulation of adhesive properties of the BM stromal microenvironment, SPARC could not only affect the fitness of B-cell precursors but also influence the BM infiltration by splenic lymphomatous cells.…”

Targeting SYK kinase‐dependent anti‐apoptotic resistance pathway in B‐lineage acute lymphoblastic leukaemia (ALL) cells with a potent SYK inhibitory pentapeptide mimic

“…RS4; 11 is a t (4; 11) BPL cell line that is exquisitely resistant to radiation (Jansen et al , 1992; Uckun & Song, 1993; Zhu & Uckun, 2000). NALM‐6 (Uckun et al , 1992, 1995) and LC1:19 (Uckun & Song, 1993; Uckun et al , 1993) are chemotherapy‐resistant BPL cell lines.…”

Polo‐like‐kinase 1 (PLK1) as a molecular target to overcome SYK‐mediated resistance of B‐lineage acute lymphoblastic leukaemia cells to oxidative stress

“…Three B‐lineage ALL cell lines were used. RAMOS is an OS‐resistant Burkitt leukaemia/B‐ALL cell line (Uckun & Song, 1993; Zhu & Uckun, 2000; Uckun et al , 2007b). RS4; 11 is a t (4; 11) pro‐B ALL cell line that is exquisitely resistant to radiation‐induced OS (Zhu & Uckun, 2000).…”

“…It has been reported that approximately one‐third of paediatric ALL cases exhibit a radiation‐resistant phenotype in vitro and OS does not cause apoptosis in their primary leukaemic cells (Uckun & Song, 1993; Uckun et al , 1993b; Weston et al , 2004; Marston et al , 2009). Increased nuclear factor (NF)κB survival pathway signalling was identified as one of the mechanisms responsible for the apoptotic resistance of B‐lineage ALL to ionising radiation (Weston et al , 2004).…”