A Role for the Bone Marrow Microenvironment in Drug Resistance of Acute Myeloid Leukemia

Bolandi, Seyed Mohammadreza; Pakjoo, Mahdi; Beigi, Peyman; Kiani, Mohammad Ali; Allahgholipour, Ali; Goudarzi, Negar; Khorashad, Jamshid S.; Eiring, Anna M.

doi:10.3390/cells10112833

Cited by 22 publications

(18 citation statements)

References 173 publications

(176 reference statements)

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“…A cell-type-specific dependence on STAT5 signaling may cause elevated susceptibility to the BCL-2- and BCL-XL inhibitors and a reduced response to PI3K- and MEK inhibitors, in the bone marrow environment. Various cellular components, cytokines, and chemokines present in the bone marrow may impact AML initiation and therapy resistance at the cellular and molecular level [ 43 , 44 ]. We found that only the combination of venetoclax and MCL1 inhibitor S63845 induced cell death with equal efficacy in AML cells grown in the absence or presence of bone marrow stroma, indicating a potential advantage of applying this combination in the treatment of AML, as this may eradicate leukemic stem cells in the bone marrow.…”

Section: Discussionmentioning

confidence: 99%

Rationale for Combining the BCL2 Inhibitor Venetoclax with the PI3K Inhibitor Bimiralisib in the Treatment of IDH2- and FLT3-Mutated Acute Myeloid Leukemia

Seipel

Brügger

Mandhair

et al. 2022

IJMS

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In October 2020, the FDA granted regular approval to venetoclax (ABT-199) in combination with hypomethylating agents for newly-diagnosed acute myeloid leukemia (AML) in adults 75 years or older, or in patients with comorbidities precluding intensive chemotherapy. The treatment response to venetoclax combination treatment, however, may be short-lived, and leukemia relapse is the major cause of treatment failure. Multiple studies have confirmed the upregulation of the anti-apoptotic proteins of the B-cell lymphoma 2 (BCL2) family and the activation of intracellular signaling pathways associated with resistance to venetoclax. To improve treatment outcome, compounds targeting anti-apoptotic proteins and signaling pathways have been evaluated in combination with venetoclax. In this study, the BCL-XL inhibitor A1331852, MCL1-inhibitor S63845, dual PI3K-mTOR inhibitor bimiralisib (PQR309), BMI-1 inhibitor unesbulin (PTC596), MEK-inhibitor trametinib (GSK1120212), and STAT3 inhibitor C-188-9 were assessed as single agents and in combination with venetoclax, for their ability to induce apoptosis and cell death in leukemic cells grown in the absence or presence of bone marrow stroma. Enhanced cytotoxic effects were present in all combination treatments with venetoclax in AML cell lines and AML patient samples. Elevated in vitro efficacies were observed for the combination treatment of venetoclax with A1331852, S63845 and bimiralisib, with differing response markers for each combination. For the venetoclax and bimiralisib combination treatment, responders were enriched for IDH2 and FLT3 mutations, whereas non-responders were associated with PTPN11 mutations. The combination of PI3K/mTOR dual pathway inhibition with bimiralisib and BCL2 inhibition with venetoclax has emerged as a candidate treatment in IDH2- and FLT3-mutated AML.

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Section: Discussionmentioning

confidence: 99%

Rationale for Combining the BCL2 Inhibitor Venetoclax with the PI3K Inhibitor Bimiralisib in the Treatment of IDH2- and FLT3-Mutated Acute Myeloid Leukemia

Seipel

Brügger

Mandhair

et al. 2022

IJMS

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“…This feature makes the T2 combo of special attention pharmaceutically because BM is a tissue where most of the leukemic stem cells reside, and blast cells stop further development, thereby protecting leukemia cells against the cytotoxicity of chemotherapeutic agents and becoming a possible source of relapse. Moreover, BM has been implicated as a privileged microenvironment in resistance to leukemia therapy [ 25 ]. The specific activity of the T2 combo in BM and blood makes this combination highly effective to treat leukemia systematically.…”

Section: Discussionmentioning

confidence: 99%

TPEN/TPGS (T2) combo dramatically reduces Philadelphia chromosome-positive pro-lymphoblastic B leukemia in BALB/c mice

2022

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Acute lymphoblastic leukemia (ALL) is hematological neoplasia that affects human beings from early life to adulthood. Although ALL treatment has been effective, an important percentage of ALL patients are resilient to treatment. Therefore, there is an urgent need for testing a new combination of compounds for the treatment of this disease. Recently, combined TPEN and TPGS (T2 combo) have shown selective cytotoxic effects in vitro leukemia cells such as Jurkat, K562, and Ba/F3 cells. In this study, we aimed to test the effect of combined TPEN and TPGS agents (T2 combo) at a fixed dose (TPEN 5 mg/kg: TPGS 100 mg/kg) on leukemic Ba/F3-BCR-ABL P210 BALB-c mice model. We found that 4 successive 2-day apart intravenous injections of T2 combo showed a statistically significant reduction of Ba/F3 BCR-ABL leukemia cells (− 69%) in leukemia BALB/c mice (n = 6) compared to untreated leukemia group (n = 6). Moreover, the T2 combo was innocuous to non-leukemia BALB/c mice (n = 3) compared to untreated non-leukemia mice (control, n = 3). After treatments (day 42), all mice were left to rest until day 50. Outstandingly, the leukemia BALB/c mice treated with the T2 combo showed a lower percentage of Ba/F3-BCR-ABL P210 cells (− 84%) than untreated leukemia BALB/c mice. Furthermore, treatment of leukemia and non-leukemia mice with T2 combo showed no significant tissue alteration/damage according to the histopathological analysis of brain, heart, liver, kidney, and spleen samples; however, T2 combo significantly reduced the number of leukocytes in the bone marrow of treated leukemia mice. We conclude that the T2 combo specifically affects leukemia cells but no other tissue/organs. Therefore, we anticipate that the T2 combo might be a potential pro-oxidant combination for the treatment of leukemia patients.

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“…MSCs confer drug resistance to AML cells through a wide variety of mechanisms where the participation of the repertoire of soluble factors and cell interactions is well known [ 258 ]. These VLA-4/VCAM1-mediated interactions [ 204 ] promote AML cells’ chemoresistance by diverse mechanisms, including Bcl-2 overexpression [ 132 ] and JAK/STAT [ 259 ] and NF-κB signalling in MSCs.…”

Section: Msc Roles In Drug Resistancementioning

confidence: 99%

“…Of note, this profile was associated with bad prognosis in AML patients [ 272 ], suggesting that the secretory phenotype of MSCs could exert an important role in the course of the disease. A detailed network participating in AML resistance has been described [ 258 ].…”

Section: Msc Roles In Drug Resistancementioning

confidence: 99%

Bone Marrow Aging and the Leukaemia-Induced Senescence of Mesenchymal Stem/Stromal Cells: Exploring Similarities

Ruiz-Aparicio

Vernot

2022

JPM

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Bone marrow aging is associated with multiple cellular dysfunctions, including perturbed haematopoiesis, the propensity to haematological transformation, and the maintenance of leukaemia. It has been shown that instructive signals from different leukemic cells are delivered to stromal cells to remodel the bone marrow into a supportive leukemic niche. In particular, cellular senescence, a physiological program with both beneficial and deleterious effects on the health of the organisms, may be responsible for the increased incidence of haematological malignancies in the elderly and for the survival of diverse leukemic cells. Here, we will review the connection between BM aging and cellular senescence and the role that these processes play in leukaemia progression. Specifically, we discuss the role of mesenchymal stem cells as a central component of the supportive niche. Due to the specificity of the genetic defects present in leukaemia, one would think that bone marrow alterations would also have particular changes, making it difficult to envisage a shared therapeutic use. We have tried to summarize the coincident features present in BM stromal cells during aging and senescence and in two different leukaemias, acute myeloid leukaemia, with high frequency in the elderly, and B-acute lymphoblastic leukaemia, mainly a childhood disease. We propose that mesenchymal stem cells are similarly affected in these different leukaemias, and that the changes that we observed in terms of cellular function, redox balance, genetics and epigenetics, soluble factor repertoire and stemness are equivalent to those occurring during BM aging and cellular senescence. These coincident features may be used to explore strategies useful to treat various haematological malignancies.

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A Role for the Bone Marrow Microenvironment in Drug Resistance of Acute Myeloid Leukemia

Cited by 22 publications

References 173 publications

Rationale for Combining the BCL2 Inhibitor Venetoclax with the PI3K Inhibitor Bimiralisib in the Treatment of IDH2- and FLT3-Mutated Acute Myeloid Leukemia

Rationale for Combining the BCL2 Inhibitor Venetoclax with the PI3K Inhibitor Bimiralisib in the Treatment of IDH2- and FLT3-Mutated Acute Myeloid Leukemia

TPEN/TPGS (T2) combo dramatically reduces Philadelphia chromosome-positive pro-lymphoblastic B leukemia in BALB/c mice

Bone Marrow Aging and the Leukaemia-Induced Senescence of Mesenchymal Stem/Stromal Cells: Exploring Similarities

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