Blockade of BCL-2 proteins efficiently induces apoptosis in progenitor cells of high-risk myelodysplastic syndromes patients

Abstract

Deregulated apoptosis is an identifying feature of myelodysplastic syndromes (MDS). Whereas apoptosis is increased in the bone marrow (BM) of low-risk MDS patients, progression to high-risk MDS correlates with an acquired resistance to apoptosis and an aberrant expression of BCL-2 proteins. To overcome the acquired apoptotic resistance in high-risk MDS, we investigated the induction of apoptosis by inhibition of pro-survival BCL-2 proteins using the BCL-2/-XL/-W inhibitor ABT-737 or the BCL-2-selective inhibitor ABT-199. We characterized a cohort of 124 primary human BM samples from MDS/secondary acute myeloid leukemia (sAML) patients and 57 healthy, age-matched controls. Inhibition of anti-apoptotic BCL-2 proteins was specifically toxic for BM cells from high-risk MDS and sAML patients, whereas low-risk MDS or healthy controls remained unaffected. Notably, ABT-737 or ABT-199 treatment was capable of targeting the MDS stem/progenitor compartment in high-risk MDS/sAML samples as shown by the reduction in CD34(+) cells and the decreased colony-forming capacity. Elevated expression of MCL-1 conveyed resistance against both compounds. Protection by stromal cells only partially inhibited induction of apoptosis. Collectively, our data show that the apoptotic resistance observed in high-risk MDS/sAML cells can be overcome by the ABT-737 or ABT-199 treatment and implies that BH3 mimetics might delay disease progression in higher-risk MDS or sAML patients.

BCR signaling inhibitors differ in their ability to overcome Mcl-1–mediated resistance of CLL B cells to ABT-199

“…Interestingly, although Mcl-1 had previously been shown to confer resistance to ABT-737 and ABT-199 in other hematological malignancies and solid tumors, 10,[18][19][20]43,44 its role in mediating resistance in CLL had remained somewhat controversial. For example, in the study of Vogler et al, 15 induction of Mcl-1 expression by stimulation with interleukin-4 or interferon-g was associated with only marginal protection, prompting the authors to conclude that resistance to ABT-737 in CLL is largely Mcl-1 independent.…”

“…17 Previous studies by our group have shown that sustained engagement of the BCR induces Mcl-1, 6 and high levels of Mcl-1 were shown to inversely correlate with treatment response in the phase 1 study of ABT-263 in CLL. 12 In addition, high levels of Mcl-1 have been shown to protect other hematological malignancies and certain solid tumors from ABT-199, [18][19][20] suggesting that Mcl-1 could also confer ABT-199 resistance to CLL cells. To further explore this possibility, we evaluated whether BCR-induced Mcl-1 overexpression can protect CLL cells from ABT-199 and whether this protection can be overcome by available BCR signaling inhibitors.…”

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

“…In a transgenic model of MDS progressing to AML, treatment with ABT-737 reduced bone marrow blasts and progenitor cells by increasing apoptosis and significantly extended lifespan (113). Jilg et al demonstrated that inhibition of BCL-2 and BCL-X L with ABT-737 or specific inhibition of BCL-2 with venetoclax was toxic to bone marrow cells from high-risk MDS and secondary AML patients, whereas cells from low-risk MDS and normal, age-matched bone marrow remained largely unaffected (114). Sensitivity to ABT-737 and venetoclax was observed in samples from treatment-naïve and treatment failure patients, suggesting that the effects of BH3 mimetics depend primarily on the level of mitochondrial priming irrespective of prior treatment.…”

CK2 and PI3K are direct molecular targets of quercetin in chronic lymphocytic leukaemia

“…Similarly, overexpressed Mcl-1 can also be responsible for ABT-263 and ABT-199 resistance in CLL cells. In fact, high levels of Mcl-1 inversely correlated with treatment response in the phase I study of ABT-263 [25] and protected hematological malignancies from ABT-199 [33, 34]. …”