JAK1/2 and BCL2 inhibitors synergize to counteract bone marrow stromal cell-induced protection of AML

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

SN - 0006-4971

VL - 130

SP - 789

EP - 802

JO - Blood

JF - Blood

IS - 6

ER -