Lkb1/stk11 is a tumor suppressor in the progression of myeloproliferative neoplasms

Christian Marinaccio, Praveen Suraneni, Hamza Celik, Andrew Volk, Qiang Jeremy Wen, Te Ling, Marinka Bulic, Terra Lasho, Richard P. Koche, Christopher A. Famulare, Noushin Farnoud, Brady Stein, Michael Schieber, Sandeep Gurbuxani, David E. Root, Scott T. Younger, Ronald Hoffman, Naseema Gangat, Panagiotis Ntziachristos, Navdeep S. ChandelRoss L. Levine, Raajit K. Rampal, Grant A. Challen, Ayalew Tefferi, John D. Crispino

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

The myeloproliferative neoplasms (MPN) frequently progress to blast phase dis-ease, 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 imma-ture 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.

Original languageEnglish
Pages (from-to)1398-1410
Number of pages13
JournalCancer discovery
Volume11
Issue number6
DOIs
StatePublished - 2021

Fingerprint

Dive into the research topics of 'Lkb1/stk11 is a tumor suppressor in the progression of myeloproliferative neoplasms'. Together they form a unique fingerprint.

Cite this