2. Academic Validation
  3. LKB1/ STK11 Is a Tumor Suppressor in the Progression of Myeloproliferative Neoplasms

LKB1/ STK11 Is a Tumor Suppressor in the Progression of Myeloproliferative Neoplasms

  • Cancer Discov. 2021 Jun;11(6):1398-1410. doi: 10.1158/2159-8290.CD-20-1353.
Christian Marinaccio  # 1,  Praveen Suraneni  # 1,  Hamza Celik 2,  Andrew Volk 3,  Qiang Jeremy Wen 4,  Te Ling 4,  Marinka Bulic 1,  Terra Lasho 5,  Richard P Koche 6,  Christopher A Famulare 7,  Noushin Farnoud 7,  Brady Stein 1,  Michael Schieber 1,  Sandeep Gurbuxani 8,  David E Root 9,  Scott T Younger 9,  Ronald Hoffman 10,  Naseema Gangat 5,  Panagiotis Ntziachristos 1 11 12,  Navdeep S Chandel 1,  Ross L Levine 13,  Raajit K Rampal 7 13,  Grant A Challen 2,  Ayalew Tefferi 5,  John D Crispino 14 4
Affiliations

Affiliations

  • 1 Northwestern University, Chicago, Illinois.
  • 2 Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
  • 3 Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
  • 4 St. Jude Children's Research Hospital, Memphis, Tennessee.
  • 5 Mayo Clinic, Rochester, Minnesota.
  • 6 Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 7 Center for Hematologic Malignancies, Memorial Sloan Kettering, New York, New York.
  • 8 University of Chicago, Chicago, Illinois.
  • 9 Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
  • 10 Mt. Sinai School of Medicine, New York, New York.
  • 11 Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.
  • 12 Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
  • 13 Leukemia Service, Department of Medicine, Memorial Sloan Kettering, New York, New York.
  • 14 Northwestern University, Chicago, Illinois. [email protected].
  • # Contributed equally.
PMID: 33579786 DOI: 10.1158/2159-8290.CD-20-1353
Abstract

The myeloproliferative neoplasms (MPN) frequently progress to blast phase disease, an aggressive form of acute myeloid leukemia. To identify genes that suppress disease progression, we performed a focused CRISPR/Cas9 screen and discovered that depletion of LKB1/Stk11 led to enhanced in vitro self-renewal of murine MPN cells. Deletion of Stk11 in a mouse MPN model caused rapid lethality with enhanced fibrosis, osteosclerosis, and an accumulation of immature cells in the bone marrow, as well as enhanced engraftment of primary human MPN cells in vivo. LKB1 loss was associated with increased mitochondrial Reactive Oxygen Species and stabilization of HIF1α, and downregulation of LKB1 and increased levels of HIF1α were observed in human blast phase MPN specimens. Of note, we observed strong concordance of pathways that were enriched in murine MPN cells with LKB1 loss with those enriched in blast phase MPN patient specimens, supporting the conclusion that STK11 is a tumor suppressor in the MPNs. SIGNIFICANCE: Progression of the myeloproliferative neoplasms to acute myeloid leukemia occurs in a substantial number of cases, but the genetic basis has been unclear. We discovered that loss of LKB1/STK11 leads to stabilization of HIF1a and promotes disease progression. This observation provides a potential therapeutic avenue for targeting progression.This article is highlighted in the In This Issue feature, p. 1307.

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