Figure 3. Combinations of targeted drugs may overcome drug resistance in MCL CD34⁺/CD38⁻ cells.

(A-D) Primary leukemic cells obtained from patients with MCL (n=5) or ASM (n=4) (A, B) or ROSA^{KIT D816V} cells (C, D) were incubated in the absence or presence of GO (A, C, left panel) or midostaurin (A, C, right panel) or a combination of both drugs (B, D) at 37°C for 48 hours. Bars represent the percentage of Annexin-V⁺ cells (A, B: gated for CD34⁺/CD38⁻ cells) after drug exposure and are expressed as mean±S.D. of all experiments. (E) Primary MCL cells (patients #1 and #7) were incubated in control medium or GO (5 μg/ml), midostaurin (1 μM) or a combination of both drugs at 37°C for 1 hour. Then, cells were injected into NSG_hSCF mice. Bars show the percentage of huKIT⁺ cells found in the murine BM after 10 weeks. (F) The percentage of CD34⁺CD38⁻ cells among all CD45⁺ cells was determined in BM samples of 2 patients treated with midostaurin (100-200 mg/day), 5 receiving cladribine (0.1-0.13 mg/kg/day over 7 days per cycle), 1 patient receiving fludarabine (30 mg/m² per day, days 1-5) and cytarabine (2.000 mg/m² per day, days 1-5), and 1 patient receiving fludarabine (30 mg/m² per day, days 1-5), cytarabine (2.000 mg/m² per day, days 1-5), and gemtuzumab-ozogamicin (2 injections of 5 mg on day 1 and day 7). BM cells were examined before therapy and during/after therapy (median follow-up: 7.86 months, range: 1.6-33.3 months). Sample details are summarized in Table S1B.