BONE MARROW SITES DIFFERENTLY IMPRINT DORMANCY AND CHEMORESISTANCE TO T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA
Author(s): ,
F Pflumio
Affiliations:
INSERM,Fontenay-aux-roses,France
,
Julien Calvo
Affiliations:
INSERM,Fontenay-aux-roses,France
,
Xavier Cahu
Affiliations:
INSERM,Fontenay-aux-roses,France
,
Sandrine Poglio
Affiliations:
INSERM,Fontenay-aux-roses,France
,
Marie-Laure Arcangeli
Affiliations:
INSERM,Fontenay-aux-roses,France
,
Thierry Leblanc
Affiliations:
INSERM,Fontenay-aux-roses,France
,
Paola Ballerini
Affiliations:
AP-HP Hôpital Trousseau,Paris,France
,
Andre Baruchel
Affiliations:
AP-HP Hôpital R Debré,Paris,France
,
Judith Landman-Parker
Affiliations:
AP-HP Hôpital Trousseau,Paris,France
,
Eric Delabesse
Affiliations:
CHU Toulouse,Toulouse,France
Benjamin Uzan
Affiliations:
INSERM,Fontenay-aux-roses,France
(Abstract release date: Jun 8, 2017) EHA Learning Center. Pflumio F. Jun 25, 2017; 183931
Disclosure(s): My lab is part of a small network granted by Sanofi company
Dr. Françoise Pflumio
Dr. Françoise Pflumio
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Abstract
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Abstract: LB2606

Type: Late Breaking Oral Session

Presentation during EHA22: On Sunday, June 25, 2017 from 11:45 - 12:00

Location: Hall A

Background
T-cell acute lymphoblastic leukemia (T-ALL) is a disease of T-cell progenitors, which mainly affects children and young adults. Numerous genomic alterations such as NOTCH1/FBXW7 mutations, TLX1/3 overexpression or SIL-TAL1 deletion are known to induce survival, proliferation and differentiation block in T-ALL cells. Interactions between leukemic cells and their microenvironment also contribute to T-ALL pathogenesis. Cell-cell contacts - Delta-Like/Jagged-Notch1, integrin LFA1/ICAM1 - and secreted factors - such as interleukin 7 and 18 or CXCL12 - are key players in T-ALL development. In the course of the disease, T-ALL cells settle in various environments such as thymus, blood, bone marrow (BM), pleura or lymph nodes, which differ in terms of cell content, extra-cellular matrix and secreted factors. To which extent these distinct niches imprint niche-specific features on T-ALL cells is not well understood.

Aims
Compare the growth of leukemic cells from human and mouse T-ALL in various BM sites. Uncover novel mechanisms of chemoresistance, in relation with the BM microenvironment.

Methods
We used grafts of human and mouse T-ALL in immune-deficient and normal mice, respectively. We explored the behavior of leukemic cells ex-vivo and in vivo after they had engrafted different BM sites of the mouse body (femurs, Thorax and Tail vertebraes). We tested their respective chemoresistance to conventional drugs (dexamethasone, vincristine, cytarabine).

Results
We observed that mouse and human T-ALL develop slowly in tail vertebrae BM compared to thorax vertebrae and femur BM. T-ALL recovered from tail BM display lower cell surface marker expression and decreased metabolism and cell cycle progression, demonstrating a dormancy phenotype. Functionally tail-derived T-ALL exhibit a deficient short-term ex vivo growth and a delayed in vivo propagation. These features are non-cell autonomous as T-ALL from tail and thorax share identical genomic abnormalities and functional disparities disappear in vivo and in prolonged in vitro assays. Importantly tail-derived T-ALL display higher intrinsic resistance to cell cycle-related drugs, i.e. vincristine sulfate and cytarabine, but not to dexamethasone. T-ALL recovered from gonadal adipose tissues or from co-cultures with adipocytes share metabolic, cell cycle and phenotypic or chemoresistance features with Tail-derived T-ALL.

Conclusion
These results demonstrate that BM sites differentially orchestrate T-ALL propagation. T-ALL derived from adipocyte–rich BM are associated with quiescence and decreased response to cell cycle dependent chemotherapy indicating that adipocyte-rich aged BM or pathologies enhancing BM adipocyte content may help leukemia escaping drug treatment.

Session topic: 1. Acute lymphoblastic leukemia - Biology

Keyword(s): Bone microenvironment, Chemoresistance, Leukemia, T-ALL

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