Targeting Apoptosis Pathways With BCL2 and MDM2 Inhibitors in Adult B-cell Acute Lymphoblastic Leukemia

Helena Hohtari; Matti Kankainen; Shady Adnan-Awad; Bhagwan Yadav; Swapnil Potdar; Aleksandr Ianevski; Olli Dufva; Caroline Heckman; Veronika Sexl; Soili Kytölä; Satu Mustjoki; Kimmo Porkka

doi:10.1097/HS9.0000000000000701

Targeting Apoptosis Pathways With BCL2 and MDM2 Inhibitors in Adult B-cell Acute Lymphoblastic Leukemia

Hemasphere. 2022 Feb 24;6(3):e701. doi: 10.1097/HS9.0000000000000701. eCollection 2022 Mar.

Authors

Helena Hohtari^{1

2}, Matti Kankainen^{1

2

3

4

5}, Shady Adnan-Awad^{1

2

6}, Bhagwan Yadav^{1

2}, Swapnil Potdar⁷, Aleksandr Ianevski⁷, Olli Dufva^{1

2

5}, Caroline Heckman^{5

7}, Veronika Sexl⁸, Soili Kytölä^{3

4}, Satu Mustjoki^{1

2

5

9}, Kimmo Porkka^{1

2

5}

Affiliations

¹ Translational Immunology Research Program, University of Helsinki, Finland.
² Hematology Research Unit Helsinki, University of Helsinki, and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
³ Laboratory of Genetics, HUS Diagnostic Center, Hospital District of Helsinki and Uusimaa (HUS), Helsinki, Finland.
⁴ Medical and Clinical Genetics, University of Helsinki, Helsinki University Hospital, Helsinki, Finland.
⁵ iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland.
⁶ Clinical and Chemical Pathology Department, National Cancer Institute, Cairo University, Giza, Egypt.
⁷ Institute for Molecular Medicine Finland, University of Helsinki, Finland.
⁸ Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Austria.
⁹ Department of Clinical Chemistry, University of Helsinki, Finland.

Abstract

In adult patients, the treatment outcome of acute lymphoblastic leukemia (ALL) remains suboptimal. Here, we used an ex vivo drug testing platform and comprehensive molecular profiling to discover new drug candidates for B-ALL. We analyzed sensitivity of 18 primary B-ALL adult patient samples to 64 drugs in a physiological concentration range. Whole-transcriptome sequencing and publicly available expression data were used to examine gene expression biomarkers for observed drug responses. Apoptotic modulators targeting BCL2 and MDM2 were highly effective. Philadelphia chromosome-negative (Ph-) samples were sensitive to both BCL2/BCL-W/BCL-XL-targeting agent navitoclax and BCL2-selective venetoclax, whereas Ph-positive (Ph+) samples were more sensitive to navitoclax. Expression of BCL2 was downregulated and BCL-W and BCL-XL upregulated in Ph+ ALL compared with Ph- samples, providing elucidation for the observed difference in drug responses. A majority of the samples were sensitive to MDM2 inhibitor idasanutlin. The regulatory protein MDM2 suppresses the function of tumor suppressor p53, leading to impaired apoptosis. In B-ALL, the expression of MDM2 was increased compared with other hematological malignancies. In B-ALL cell lines, a combination of BCL2 and MDM2 inhibitor was synergistic. In summary, antiapoptotic proteins including BCL2 and MDM2 comprise promising targets for future drug studies in B-ALL.