JAK1/2 and BCL2 inhibitors synergize to counteract bone marrow stromal cell-induced protection of AML
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JAK1/2 and BCL2 inhibitors synergize to counteract bone marrow stromal cell-induced protection of AML. / Karjalainen, Riikka; Pemovska, Tea; Popa, Mihaela; Liu, Minxia; Javarappa, Komal K; Majumder, Muntasir M; Yadav, Bhagwan; Tamborero, David; Tang, Jing; Bychkov, Dmitrii; Kontro, Mika; Parsons, Alun; Suvela, Minna; Mayoral Safont, Mireia; Porkka, Kimmo; Aittokallio, Tero; Kallioniemi, Olli; McCormack, Emmet; Gjertsen, Bjørn T; Wennerberg, Krister; Knowles, Jonathan; Heckman, Caroline A.
In: Blood, Vol. 130, No. 6, 10.08.2017, p. 789-802.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - JAK1/2 and BCL2 inhibitors synergize to counteract bone marrow stromal cell-induced protection of AML
AU - Karjalainen, Riikka
AU - Pemovska, Tea
AU - Popa, Mihaela
AU - Liu, Minxia
AU - Javarappa, Komal K
AU - Majumder, Muntasir M
AU - Yadav, Bhagwan
AU - Tamborero, David
AU - Tang, Jing
AU - Bychkov, Dmitrii
AU - Kontro, Mika
AU - Parsons, Alun
AU - Suvela, Minna
AU - Mayoral Safont, Mireia
AU - Porkka, Kimmo
AU - Aittokallio, Tero
AU - Kallioniemi, Olli
AU - McCormack, Emmet
AU - Gjertsen, Bjørn T
AU - Wennerberg, Krister
AU - Knowles, Jonathan
AU - Heckman, Caroline A
N1 - © 2017 by The American Society of Hematology.
PY - 2017/8/10
Y1 - 2017/8/10
N2 - The bone marrow (BM) provides a protective microenvironment to support the survival of leukemic cells and influence their response to therapeutic agents. In acute myeloid leukemia (AML), the high rate of relapse may in part be a result of the inability of current treatment to effectively overcome the protective influence of the BM niche. To better understand the effect of the BM microenvironment on drug responses in AML, we conducted a comprehensive evaluation of 304 inhibitors, including approved and investigational agents, comparing ex vivo responses of primary AML cells in BM stroma-derived and standard culture conditions. In the stroma-based conditions, the AML patient cells exhibited significantly reduced sensitivity to 12% of the tested compounds, including topoisomerase II, B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL2), and many tyrosine kinase inhibitors (TKIs). The loss of TKI sensitivity was most pronounced in patient samples harboring FLT3 or PDGFRB alterations. In contrast, the stroma-derived conditions enhanced sensitivity to Janus kinase (JAK) inhibitors. Increased cell viability and resistance to specific drug classes in the BM stroma-derived conditions was a result of activation of alternative signaling pathways mediated by factors secreted by BM stromal cells and involved a switch from BCL2 to BCLXL-dependent cell survival. Moreover, the JAK1/2 inhibitor ruxolitinib restored sensitivity to the BCL2 inhibitor venetoclax in AML patient cells ex vivo in different model systems and in vivo in an AML xenograft mouse model. These findings highlight the potential of JAK inhibitors to counteract stroma-induced resistance to BCL2 inhibitors in AML.
AB - The bone marrow (BM) provides a protective microenvironment to support the survival of leukemic cells and influence their response to therapeutic agents. In acute myeloid leukemia (AML), the high rate of relapse may in part be a result of the inability of current treatment to effectively overcome the protective influence of the BM niche. To better understand the effect of the BM microenvironment on drug responses in AML, we conducted a comprehensive evaluation of 304 inhibitors, including approved and investigational agents, comparing ex vivo responses of primary AML cells in BM stroma-derived and standard culture conditions. In the stroma-based conditions, the AML patient cells exhibited significantly reduced sensitivity to 12% of the tested compounds, including topoisomerase II, B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL2), and many tyrosine kinase inhibitors (TKIs). The loss of TKI sensitivity was most pronounced in patient samples harboring FLT3 or PDGFRB alterations. In contrast, the stroma-derived conditions enhanced sensitivity to Janus kinase (JAK) inhibitors. Increased cell viability and resistance to specific drug classes in the BM stroma-derived conditions was a result of activation of alternative signaling pathways mediated by factors secreted by BM stromal cells and involved a switch from BCL2 to BCLXL-dependent cell survival. Moreover, the JAK1/2 inhibitor ruxolitinib restored sensitivity to the BCL2 inhibitor venetoclax in AML patient cells ex vivo in different model systems and in vivo in an AML xenograft mouse model. These findings highlight the potential of JAK inhibitors to counteract stroma-induced resistance to BCL2 inhibitors in AML.
KW - Animals
KW - Antineoplastic Agents/pharmacology
KW - Bone Marrow Cells/drug effects
KW - Bridged Bicyclo Compounds, Heterocyclic/pharmacology
KW - Cell Line
KW - Drug Resistance, Neoplasm/drug effects
KW - Drug Synergism
KW - Female
KW - Humans
KW - Janus Kinase 1/antagonists & inhibitors
KW - Janus Kinase 2/antagonists & inhibitors
KW - Leukemia, Myeloid, Acute/drug therapy
KW - Mice
KW - Protein Kinase Inhibitors/pharmacology
KW - Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors
KW - Pyrazoles/pharmacology
KW - STAT Transcription Factors/metabolism
KW - Signal Transduction/drug effects
KW - Stromal Cells/drug effects
KW - Sulfonamides/pharmacology
KW - Tumor Cells, Cultured
U2 - 10.1182/blood-2016-02-699363
DO - 10.1182/blood-2016-02-699363
M3 - Journal article
C2 - 28619982
VL - 130
SP - 789
EP - 802
JO - Blood
JF - Blood
SN - 0006-4971
IS - 6
ER -
ID: 199423236