Myosin-IIA regulates leukemia engraftment and brain infiltration in a mouse model of acute lymphoblastic leukemia – Journal of Leukocyte Biology (subscription)

1. Eric J. Wigton*,¹,²,
2. Scott B. Thompson*,^†,¹,
3. Robert A. Long* and
4. Jordan Jacobelli*,^†,³

1. ^*Department of Biomedical Research, National Jewish Health, Denver, Colorado, USA; and
2. ^†Department of Immunology and Microbiology, University of Colorado School of Medicine, Denver, Colorado, USA

1. ↵3Correspondence: National Jewish Health, 1400 Jackson St., Denver, CO 80206, USA. E-mail: jacobellij{at}njhealth.org

1. ↵1 These authors contributed just as to this work.

• ↵2 Current affiliation: University of California San Francisco, California, USA.

Abstract

Leukemia dissemination (the spread of leukemia cells from the bone marrow) and relapse are associated along with bad prognosis. Often, relapse occurs in peripheral organs, such as the CNS, which acts as a sanctuary site for leukemia cells to escape anti-cancer treatments. Like typical leukocyte migration, leukemia dissemination entails migration of cells from the blood move in to tissues by extravasation. To extravasate, leukemia cells cross through vascular endothelial walls via a procedure called transendothelial migration, which calls for cytoskeletal remodeling. However, the individual molecular users in leukemia extravasation are not fully known. We examined the role of myosin-IIA a cytoskeletal class II myosin motor protein, in leukemia improvement and dissemination in to the CNS by usage of a mouse model of Bcr-Abl-steered B cell acute lymphoblastic leukemia. Small hairpin RNA-mediated depletion of myosin-IIA did not affect apoptosis or the growth price of B cell acute lymphoblastic leukemia cells. However, in an in vivo leukemia transfer model, myosin-IIA depletion slowed leukemia improvement and prolonged survival, in part, by cutting down the ability of B cell acute lymphoblastic leukemia cells to engraft efficiently. Finally, myosin-IIA inhibition, either by small hairpin RNA depletion or chemical inhibition by blebbistatin, drastically low CNS infiltration of leukemia cells. The effects on leukemia cell entry in to tissues were mostly a result of the necessity for myosin-IIA to allow leukemia cells to finish the transendothelial migration procedure throughout extravasation. Overall, our data implicate myosin-IIA as a essential mediator of leukemia cell migration, making it a promising target to inhibit leukemia dissemination in vivo and potentially lessen leukemia relapses.

Footnotes

• The online version of this paper, discovered at www.jleukbio.org, involves supplemental information.

• Abbreviations:

  7-AAD

  7-aminoactinomycin D

  ALL

  acute lymphoblastic leukemia

  APC

  allophycocyanin

  B-ALL

  B cell acute lymphoblastic leukemia

  KD

  knockdown

  MyoIIA/B/C

  myosin-II A/B/C

  PacBlue

  Pacific Blue

  shRNA

  small hairpin RNA

  TEM

  transendothelial migration

  TKI

  tyrosine kinase inhibitor

• Received August 5, 2015.
• Revision received December 31, 2015.
• Accepted January 4, 2016.

• © Society for Leukocyte Biology