Interactions between acute lymphoblastic leukemia and bone marrow stromal cells influence response to therapy

Tesfai, Yordanos; Ford, Jette; Carter, Kim W.; Firth, Martin J; O’Leary, Rebecca A.; Gottardo, Nicholas G.; Cole, Catherine; Kees, Ursula R.

doi:10.1016/j.leukres.2011.08.001

Cited by 40 publications

(41 citation statements)

References 34 publications

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“…While mouse models define the gold standard for testing questions related to drug efficacy, 2D co-culture continues to be a cost effective methodology for testing hypotheses and drug strategies related to bone morrow microenvironment support of leukemic cell survival. Many groups have shown that co-culture of leukemic cells with BMSC or OB provides a survival advantage when challenged with chemotherapy agents 9,10,[12][13][14][19][20][21] . Work modeling normal immature CD34+ hematopoietic cells in coculture with mesenchymal stem cells (MSC) revealed that hematopoietic cells will interact with the adherent monolayer of MSCs to form three distinct spatial populations of hematopoietic cells 22,23 .…”

Section: Discussionmentioning

confidence: 99%

“…Models that include leukemic cells in isolation, such as those limited to culture of cells in media alone, for testing of therapeutic approaches do not factor in these critical signals, or the heterogeneity of disease that occurs in response to availability of niche derived cues in which tumor cell subpopulations with very specific interactions with niche cells derive enhanced protection. Standard 2D coculture models that co-culture bone marrow derived stromal cells and leukemic cells have somewhat addressed the contribution of the marrow niche and have shown that interaction with bone marrow microenvironment cells increases their resistance to chemotherapy and alters their growth characteristics [9][10][11][12][13][14] . These models however often fail to recapitulate long term survival of tumor cells and do not accurately inform the outcomes associated with the most resistant leukemic cell populations that contribute to MRD.…”

Section: Introductionmentioning

confidence: 99%

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Modeling Chemotherapy Resistant Leukemia <em>In Vitro</em>

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Moses

Evans

et al. 2016

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It is well established that the bone marrow microenvironment provides a unique site of sanctuary for hematopoietic diseases that both initiate and progress in this site. The model presented in the current report utilizes human primary bone marrow stromal cells and osteoblasts as two representative cell types from the marrow niche that influence tumor cell phenotype. The in vitro co-culture conditions described for human leukemic cells with these primary niche components support the generation of a chemoresistant subpopulation of tumor cells that can be efficiently recovered from culture for analysis by diverse techniques. A strict feeding schedule to prevent nutrient fluxes followed by gel type 10 cross-linked dextran (G10) particles recovery of the population of tumor cells that have migrated beneath the adherent bone marrow stromal cells (BMSC) or osteoblasts (OB) generating a "phase dim" (PD) population of tumor cells, provides a consistent source of purified therapy resistant leukemic cells. This clinically relevant population of tumor cells can be evaluated by standard methods to investigate apoptotic, metabolic, and cell cycle regulatory pathways as well as providing a more rigorous target in which to test novel therapeutic strategies prior to pre-clinical investigations targeted at minimal residual disease. Video LinkThe video component of this article can be found at

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Modeling Chemotherapy Resistant Leukemia <em>In Vitro</em>

Slone

Moses

Evans

et al. 2016

JoVE

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“…On the basis of mounting evidence showing that stromal cells within the bone marrow microenvironment provide a proactive niche for leukemic cells [35][36][37] and lead to activation of the MAPK pathway, 38,39 we examined the sensitivity of the ALL cell lines to cytotoxic chemotherapy in combination with MEK1/2 inhibition when cocultured with human bone marrow stromal cells (BMSCs). First, we measured the levels of apoptosis in 697 cells alone or cocultured with HS-5 cells upon prednisolone treatment.…”

Section: Inhibition Of Mek1/2 Increases Sensitivity Of All Cell Linesmentioning

confidence: 99%

MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia

Jones

Gearheart

Fosmire

et al. 2015

Blood

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• Genetic or pharmacologic inhibition of MEK4 and MEK2 enhances prednisoloneinduced cell death in ALL models.• MAPK signaling cascades are activated at relapse compared to diagnosis in ALL samples and have enhanced response to MEK inhibition.The outcome for pediatric acute lymphoblastic leukemia (ALL) patients who relapse is dismal. A hallmark of relapsed disease is acquired resistance to multiple chemotherapeutic agents, particularly glucocorticoids. In this study, we performed a genome-scale short hairpin RNA screen to identify mediators of prednisolone sensitivity in ALL cell lines. The incorporation of these data with an integrated analysis of relapse-specific genetic and epigenetic changes allowed us to identify the mitogen-activated protein kinase (MAPK) pathway as a mediator of prednisolone resistance in pediatric ALL. We show that knockdown of the specific MAPK pathway members MEK2 and MEK4 increased sensitivity to prednisolone through distinct mechanisms. MEK4 knockdown increased sensitivity specifically to prednisolone by increasing the levels of the glucocorticoid receptor. MEK2 knockdown increased sensitivity to all chemotherapy agents tested by increasing the levels of p53. Furthermore, we demonstrate that inhibition of MEK1/2 with trametinib increased sensitivity of ALL cells and primary samples to chemotherapy in vitro and in vivo. To confirm a role for MAPK signaling in patients with relapsed ALL, we measured the activation of the MEK1/2 target ERK in matched diagnosis-relapse primary samples and observed increased phosphorylated ERK levels at relapse. Furthermore, relapse samples have an enhanced response to MEK inhibition compared to matched diagnosis samples in xenograft models. Together, our data indicate that inhibition of the MAPK pathway increases chemosensitivity to glucocorticoids and possibly other agents and that the MAPK pathway is an attractive target for prevention and/or treatment of relapsed disease. (Blood. 2015;126(19):2202-2212

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“…Leukemic blasts are known to modulate the bone marrow environment 70 which can lead to drug resistance in response to therapy. 71 A recent study has demonstrated rare dormant, treatment resistant stem cells. Notably in ALL, resistance is dependent on interactions with the endosteal niche; release from this environment induced proliferation and sensitised the cells to drug treatment.…”

Section: The Role Of Tumor Stem Cells In the Biology Of Relapsementioning

confidence: 99%