PMID- 32501543
OWN - NLM
STAT- MEDLINE
DCOM- 20210317
LR  - 20210317
IS  - 1096-9896 (Electronic)
IS  - 0022-3417 (Linking)
VI  - 252
IP  - 1
DP  - 2020 Sep
TI  - Upregulated expression and function of the alpha4beta1 integrin in multiple myeloma 
      cells resistant to bortezomib.
PG  - 29-40
LID - 10.1002/path.5480 [doi]
AB  - The interaction of multiple myeloma (MM) cells with the bone marrow (BM) 
      microenvironment promotes MM cell retention, survival, and resistance to 
      different anti-MM agents, including proteasome inhibitors (PIs) such as 
      bortezomib (BTZ). The alpha4beta1 integrin is a main adhesion receptor mediating MM 
      cell-stroma interactions and MM cell survival, and its expression and function 
      are downregulated by BTZ, leading to inhibition of cell adhesion-mediated drug 
      resistance (CAM-DR) and MM cell apoptosis. Whether decreased alpha4beta1 expression and 
      activity are maintained or recovered upon development of resistance to BTZ 
      represents an important question, as a potential rescue of alpha4beta1 function could 
      boost MM cell survival and disease progression. Using BTZ-resistant MM cells, we 
      found that they not only rescue their alpha4beta1 expression, but its levels were higher 
      than in parental cells. Increased alpha4beta1 expression in resistant cells correlated 
      with enhanced alpha4beta1-mediated cell lodging in the BM, and with disease progression. 
      BTZ-resistant MM cells displayed enhanced NF-kappaB pathway activation relative to 
      parental counterparts, which contributed to upregulated alpha4 expression and to 
      alpha4beta1-dependent MM cell adhesion. These data emphasize the upregulation of alpha4beta1 
      expression and function as a key event during resistance to BTZ in MM, which 
      might indirectly contribute to stabilize this resistance, as stronger MM cell 
      attachment to BM stroma will regain CAM-DR and MM cell growth and survival. 
      Finally, we found a strong correlation between high ITGB1 (integrin beta1) 
      expression in MM and poor progression-free survival (PFS) and overall survival 
      (OS) during treatment of MM patients with BTZ and IMIDs, and combination of high 
      ITGB1 levels and presence of the high-risk genetic factor amp1q causes low PFS 
      and OS. These results unravel a novel prognostic value for ITGB1 in myeloma. (c) 
      2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & 
      Sons, Ltd.
CI  - (c) 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley 
      & Sons, Ltd.
FAU - Sevilla-Movilla, Silvia
AU  - Sevilla-Movilla S
AD  - Department of Molecular Biomedicine, Centro de Investigaciones Biologicas 
      Margarita Salas (CSIC), Madrid, Spain.
FAU - Arellano-Sanchez, Nohemi
AU  - Arellano-Sanchez N
AD  - Department of Molecular Biomedicine, Centro de Investigaciones Biologicas 
      Margarita Salas (CSIC), Madrid, Spain.
FAU - Martinez-Moreno, Monica
AU  - Martinez-Moreno M
AD  - Department of Molecular Biomedicine, Centro de Investigaciones Biologicas 
      Margarita Salas (CSIC), Madrid, Spain.
FAU - Gajate, Consuelo
AU  - Gajate C
AD  - Department of Molecular Biomedicine, Centro de Investigaciones Biologicas 
      Margarita Salas (CSIC), Madrid, Spain.
FAU - Sanchez-Vencells, Anna
AU  - Sanchez-Vencells A
AD  - Department of Molecular Biomedicine, Centro de Investigaciones Biologicas 
      Margarita Salas (CSIC), Madrid, Spain.
FAU - Valcarcel, Luis V
AU  - Valcarcel LV
AD  - Centro de Investigacion Medica Aplicada, Universidad de Navarra, Pamplona, Spain.
FAU - Agirre, Xabier
AU  - Agirre X
AD  - Centro de Investigacion Medica Aplicada, Universidad de Navarra, Pamplona, Spain.
FAU - Valeri, Antonio
AU  - Valeri A
AD  - Department of Translational Hematology, Hospital Universitario 12 de Octubre, 
      Centro Nacional de Investigaciones Oncologicas, CIBERONC, Madrid, Spain.
FAU - Martinez-Lopez, Joaquin
AU  - Martinez-Lopez J
AD  - Department of Translational Hematology, Hospital Universitario 12 de Octubre, 
      Centro Nacional de Investigaciones Oncologicas, CIBERONC, Madrid, Spain.
FAU - Prosper, Felipe
AU  - Prosper F
AD  - Centro de Investigacion Medica Aplicada, Universidad de Navarra, Pamplona, Spain.
AD  - Department of Hematology, Clinica Universidad de Navarra, Universidad de Navarra, 
      Pamplona, Spain.
FAU - Mollinedo, Faustino
AU  - Mollinedo F
AD  - Department of Molecular Biomedicine, Centro de Investigaciones Biologicas 
      Margarita Salas (CSIC), Madrid, Spain.
FAU - Teixido, Joaquin
AU  - Teixido J
AUID- ORCID: 0000-0002-3177-4151
AD  - Department of Molecular Biomedicine, Centro de Investigaciones Biologicas 
      Margarita Salas (CSIC), Madrid, Spain.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200722
PL  - England
TA  - J Pathol
JT  - The Journal of pathology
JID - 0204634
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Integrin alpha4beta1)
RN  - 69G8BD63PP (Bortezomib)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*administration & dosage
MH  - Bortezomib/*administration & dosage
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Drug Resistance, Neoplasm/*genetics
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Integrin alpha4beta1/genetics/*metabolism
MH  - Mice
MH  - Multiple Myeloma/genetics/*metabolism/pathology
MH  - Tumor Microenvironment
OTO - NOTNLM
OT  - integrins
OT  - multiple myeloma
OT  - prognosis
OT  - proteasome inhibitors
OT  - resistance
EDAT- 2020/06/06 06:00
MHDA- 2021/03/18 06:00
CRDT- 2020/06/06 06:00
PHST- 2020/02/06 00:00 [received]
PHST- 2020/04/29 00:00 [revised]
PHST- 2020/05/28 00:00 [accepted]
PHST- 2020/06/06 06:00 [pubmed]
PHST- 2021/03/18 06:00 [medline]
PHST- 2020/06/06 06:00 [entrez]
AID - 10.1002/path.5480 [doi]
PST - ppublish
SO  - J Pathol. 2020 Sep;252(1):29-40. doi: 10.1002/path.5480. Epub 2020 Jul 22.