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 language | English (US) |
|---|---|
| Pages (from-to) | 1398-1410 |
| Number of pages | 13 |
| Journal | Cancer discovery |
| Volume | 11 |
| Issue number | 6 |
| DOIs | |
| State | Published - 2021 |
Funding
This work was supported by the NIH grants R01CA237039 and R01HL112792 to J.D. Crispino, R01HL147978 to G.A. Challen, R35CA197532 to N.S. Chandel, R01CA248770 to P. Ntziachristos, R50CA211534 to Q.J. Wen, and the MPN Research Consortium P01CA108671 to R. Hoffman, R.L. Levine, J.D. Crispino, and R.K. Rampal. A. Volk was supported by K99CA230314, R.K. Rampal is supported by K08CA188529-01, and M. Schieber was supported by the Northwestern University Physician Scientist Training Program as well as by a Conquer Cancer Young Investigator Award. We also acknowledge the support of Memorial Sloan Kettering Cancer Center Support Grant NIH P30 CA008748. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. G.A. Challen is a scholar of the Leukemia and Lymphoma Society. H. Celik was supported by an Edward P. Evans Foundation Young Investigator Award, the Leukemia Research Foundation, and the When Everyone Survives Foundation. Additional support was provided by the Janus Fund (R.L. Levine), the Samuel Waxman Cancer Research Foundation (J.D. Crispino), and St. Jude/ALSAC (J.D. Crispino). B. Stein reports other support from Pharmaessentia and Constellation outside the submitted work. D.E. Root reports grants from AbbVie, Bristol-Myers Squibb, Janssen, Merck, and Vir outside the submitted work. N.S. Chandel reports personal fees from Rafael Pharma outside the submitted work. R.L. Levine reports personal fees and other support from Qiagen and C4, personal fees from Lilly and Janssen, and other support from Prelude, Zentalis, Isoplexis, Mission Bio, Ajax, and Auron outside the submitted work. R.K. Rampal reports grants and personal fees from Constellation, Incyte, Celgene/ BMS, and Stemline personal fees from Promedior, CTI, Blueprint, Galecto, Pharmaessentia, and AbbVie outside the submitted work. G.A. Challen reports grants from Incyte outside the submitted work. J.D. Crispino reports grants from NIH, Samuel Waxman Cancer Research Foundation, and ALSAC during the conduct of the study. No disclosures were reported by the other authors.
ASJC Scopus subject areas
- Oncology
