Involvement of BAFF and APRIL in Resistance to Apoptosis of Acute Myeloid Leukemia

Abstract

B-cell activation factor of the TNF family (BAFF), and a proliferation-inducing ligand (APRIL), two members of the tumour necrosis factor (TNF) superfamily, beyond playing a significant role in normal B-cell development, promote survival and proliferation of malignant B cells. Both ligands interact with 3 receptors: BAFF-R, specific to BAFF, and TACI and BCMA which are shared by both BAFF and APRIL. Here we wished to investigate the potential role of these proteins in resistance of acute myeloid leukaemia (AML) blasts to apoptosis. We found that the levels of both mRNA and proteins of APRIL, BAFF and their receptors were expressed in leukaemic cells of 24 newly diagnosed, untreated AML patients. We also demonstrated that patients who did not further respond to induction therapy (NR) presented with significantly higher baseline APRIL and BAFF expression on AML blasts as compared to these subjects who, after induction, achieved complete remission (CR) following induction therapy. Moreover, we observed striking differences in baseline levels of BCMA between CR and NR patients as we did not find detectable expression of this receptor in the latter group of patients. Interestingly, we found that AML blasts collected at baseline from NR patients cultured in presence of exogenous BAFF and APRIL were significantly more resistant to spontaneous or drug-induced apoptosis as compared with cells derived from CR patients. Altogether, our data confirm that BAFF and APRIL signaling play important role in AML pathogenesis and susceptibility to cytotoxic therapy while measuring of BCMA expression on AML cells can become a novel prognostic factor for chemotherapy response.

B-cell maturation antigen expression across hematologic cancers: a systematic literature review

“…In a Polish study of 24 patients with newly diagnosed AML, cell surface BCMA protein expression was assessed in patient-derived PBMCs 29 . Patient AML ranged from minimally differentiated to acute myelomonocytic leukemia.…”

“…BCMA was detected in 36/36 (100%) primary B-ALL specimens and in 4/6 (67%) B-ALL lines. In the study by Bolkun et al 29 , BCMA mRNA expression was assessed in patient-derived PBMCs from 24 patients with newly diagnosed AML 29 . BCMA mRNA expression was higher in CR vs. NR patients (8.16 ± 5.20 vs. 0.12 ± 0.03, p = 0.0127), as determined by qPCR.…”

“…For leukemia, 4/5 (80%) identified studies reported BCMA expression at varying levels 11,24,[28][29][30] . B-ALL samples were generally BCMA-positive, with 100% of patientderived BMCs and B-ALL cells expressing BCMA mRNA in two studies 11,30 .…”

Correlation of APRIL with production of inflammatory cytokines during acute malaria in the Brazilian Amazon

“…The APRIL and/or BAFF plasma levels are upregulated in many noninfectious [26,[68][69][70][71][72][73][74][75][76] and infectious diseases [32,73,77,78], including malaria [36,54] that are often accompanied by polyclonal B-cell activation, hypergammaglobulinemia, autoimmune disorders and lymphopenia. In malaria, polyclonal B-cell activation has been shown in the acute phase of P. vivax and P. falciparum malaria [15], which decreases 5-15 days after the beginning of treatment [15], with similar transient kinetics of IL-10, APRIL and/or BAFF levels, observed in our study.…”

Prognostic significance of Notch ligands in patients with non-small cell lung cancer

“…The TaqMan probes (Hs01070032_ m1 Jag1, Hs00171432_m1 Jag2, Hs00194509_m1 Dll1, Hs01085096_m1 Dll3, Hs00184092_m1 Dll4, Hs00172878_m1 Hes1, Hs01062014_m1 Notch1) and the TaqMan Assay kit (all from Applied Biosystems; Thermo Fisher Scientific, Inc.) were used to perform PCR. The expression of the above-mentioned genes [by the change-in-cycling-threshold ΔCq method (18,19)] were calculated and normalized to ribosomal 18SRNA gene expression (Hs99999901_s1 18SRNA). The following thermocycling conditions were used: 50˚C for 2 min; 95˚C for 10 min; 40 cycles of 95˚C for 15 sec and 60˚C for 60 sec.…”