Page 157 - 2021_04-Haematologica-web

SYK inhibition for infant ALL
SYK as a potential therapeutic target. Preclinical studies have shown that SYK inhibition can attenuate the growth of B-ALL in vitro and in vivo regardless of pre-BCR expres- sion or genetic subtype.26,29 Mohr et al. also recently report- ed that HOXA9/MEIS1-induced upregulation of SYK is a major driver of leukemogenesis in AML.25 Several early phase clinical trials are now testing the safety and poten-
tial efficacy of ENTO in combination with chemotherapy in adults with relapsed or refractory leukemias (clinicaltri- als.gov identifiers: NCT02404220, NCT02343939, NCT03135028). Interim results from these studies have reported manageable adverse events and remarkable response rates, particularly in patients with KMT2A-R AML (clinicaltrials.gov identifier: NCT02343939).33
A
B
Figure 4. HOXA9 and MEIS1 expression signatures of KMT2A-R and non-KMT2A-R acute lymphoblastic leukemia (ALL) patient-derived xenograft (PDX) specimens. (A) Splenic PDX samples were analyzed for expression of mRNA for HOXA9 and MEIS1 by NanoString, with human bone marrow mononuclear cells (BMMC) and KG- 1 cell line as negative and positive controls, respectively. Increased MEIS1 and/or HOXA9 expression was seen in KMT2A-R ALL PDX models versus non-KMT2A-R (WT) models and generally clustered by genetic subtype. (B) Total and phosphorylated signal transduction proteins from murine splenic lysates were evaluated using Simple Western. Basal kinase signaling activation differed among KMT2A-R and non-KMT2A-R ALL samples and stratified by genetic subgroup (KMT2A-AFF1, KMT2A-MLLT1, KMT2A-MLLT3, and non-KMT2A-R). β-actin was used as a protein loading control.
haematologica | 2021; 106(4)
1073