Selective inhibition of BCL-2 is a promising target in patients with high-risk myelodysplastic syndromes and adverse mutational profile

Abstract

Somatic mutations in genes such as ASXL1, RUNX1, TP53 or EZH2 adversely affect the outcome of patients with myelodysplastic syndromes (MDS). Since selective BCL-2 inhibition is a promising treatment strategy in hematologic malignancies, we tested the therapeutic impact of ABT-199 on MDS patient samples bearing an adverse mutational profile. By gene expression, we found that the level of pro-apoptotic BIM significantly decreased during MDS disease progression in line with an acquired resistance to cell death. Supporting the potential for ABT-199 treatment in MDS, high-risk MDS patient samples specifically underwent cell death in response to ABT-199 even when harbouring mutations in ASXL1, RUNX1, TP53 or EZH2. ABT-199 effectively targeted the stem- and progenitor compartment in advanced MDS harbouring mutations in ASXL1, RUNX1, TP53 or EZH2 and even proved effective in patients harbouring more than one of the defined high-risk mutations. Moreover, we utilized the protein abundance of BCL-2 family members in primary patient samples using flow cytometry as a biomarker to predict ABT-199 treatment response. Our data demonstrate that ABT-199 effectively induces apoptosis in progenitors of high-risk MDS/sAML despite the presence of adverse genetic mutations supporting the notion that pro-apoptotic intervention will hold broad therapeutic potential in high-risk MDS patients with poor prognosis.

MCL1 dependence across MDS subtypes and dual inhibition of MCL1 and BCL2 in MISTRG6 mice

“…Nonetheless, we have performed a comprehensive analysis on a cohort of MDS patient samples to investigate the value of targeting anti-apoptotic proteins for the treatment of MDS. Overall, our data validated previous findings that higher blast count MDS subtypes (EB1 and EB2) are more sensitive to VEN monotherapy than low blast count subtypes 1,4 and that mutations associated with VEN resistance in AML may be similarly relevant in MDS. We also discovered, importantly, that MCL1 inhibtion may be effective for all MDS subtypes.…”

“…While few samples were sensitive to BCL-X L inhibition (A-1155463), we observed a range of sensitivities to BCL2 inhibition that positively correlated with blast count. Consistent with previous findings, 1,4 lower blast count MDS (RS-SLD/MLD and MLD) exhibited less sensitivity than higher blast count (EB1 and EB2) MDS subtypes (P = 0.01) ( Supplementary Figure 1a). All subtypes were sensitive to the selective MCL1 inhibitor, S63845.…”

Transcriptional Silencing of MCL-1 Through Cyclin-Dependent Kinase Inhibition in Acute Myeloid Leukemia

“…Overexpression of MCL-1 is recognized as having a critical role in several hematologic malignancies including diffuse large B-cell lymphoma (47), multiple myeloma (MM) (48), chronic lymphocytic lymphoma (49), and in AML cell survival and treatment resistance (50)(51)(52). Further, increased MCL-1 expression is associated with treatment resistance to myelodysplastic syndrome (MDS) (53,54), which can evolve into AML. Preclinical studies support the potential for inhibition of MCL-1 to attenuate the underlying pathogenesis of AML (48,50,51,(55)(56)(57)(58)(59), including when used in combination with BCL-2 and/or BCL2L1 (also known as BCL-X L ) inhibition (60)(61)(62)(63)(64).…”

Myelodysplastic Syndrome with Transfusion Dependence Treated with Venetoclax

“…Venetoclax, a small molecule inhibitor of the antiapoptotic protein BCL-2, has demonstrated promising results as a monotherapy in high-risk MDS/AML in in vitro studies [8,9] and is currently being evaluated in clinical trials as a single-agent and in combination with Azacitidine for relapsed/refractory MDS. In this case, we describe a patient with transfusion-dependent myelodysplastic syndrome refractory to the current standard of care treatments and not a candidate for hematopoietic cell transplantation who responded well to monotherapy treatment with Venetoclax and has since remained transfusion-independent.…”