Mutated Ptpn11 alters leukemic stem cell frequency and reduces the sensitivity of acute myeloid leukemia cells to Mcl1 inhibition Journal Article

   

Authors:	Chen, L.; Chen, W.; Mysliwski, M.; Serio, J.; Ropa, J.; Abulwerdi, F. A.; Chan, R. J.; Patel, J. P.; Tallman, M. S.; Paietta, E.; Melnick, A.; Levine, R. L.; Abdel-Wahab, O.; Nikolovska-Coleska, Z.; Muntean, A. G.
Article Title:	Mutated Ptpn11 alters leukemic stem cell frequency and reduces the sensitivity of acute myeloid leukemia cells to Mcl1 inhibition
Abstract:	PTPN11 encodes the Shp2 non-receptor protein-tyrosine phosphatase implicated in several signaling pathways. Activating mutations in Shp2 are commonly associated with juvenile myelomonocytic leukemia but are not as well defined in other neoplasms. Here we report that Shp2 mutations occur in human acute myeloid leukemia (AML) at a rate of 6.6% (6/91) in the ECOG E1900 data set. We examined the role of mutated Shp2 in leukemias harboring MLL translocations, which co-occur in human AML. The hyperactive Shp2E76K mutant, commonly observed in leukemia patients, significantly accelerated MLL-AF9-mediated leukemogenesis in vivo. Shp2E76K increased leukemic stem cell frequency and affords MLL-AF9 leukemic cells IL3 cytokine hypersensitivity. As Shp2 is reported to regulate anti-apoptotic genes, we investigated Bcl2, Bcl-xL and Mcl1 expression in MLL-AF9 leukemic cells with and without Shp2E76K. Although the Bcl2 family of genes was upregulated in Shp2E76K cells, Mcl1 showed the highest upregulation in MLL-AF9 cells in response to Shp2E76K. Indeed, expression of Mcl1 in MLL-AF9 cells phenocopies expression of Shp2E76K, suggesting Shp2 mutations cooperate through activation of anti-apoptotic genes. Finally, we show Shp2E76K mutations reduce sensitivity of AML cells to small-molecule-mediated Mcl1 inhibition, suggesting reduced efficacy of drugs targeting MCL1 in patients with hyperactive Shp2. © 2015 Macmillan Publishers Limited.
Keywords:	gene mutation; gene translocation; human cell; nonhuman; genetic analysis; mouse; protein bcl 2; enzyme inhibition; gene expression; animal experiment; in vivo study; protein bcl xl; stem cell; protein mcl 1; leukemia cell; leukemogenesis; acute myeloblastic leukemia; gene silencing; short hairpin rna; protein tyrosine phosphatase shp 2; leukemia stem cell; interleukin 3; human; female; priority journal; article
Journal Title:	Leukemia
Volume:	29
Issue:	6
ISSN:	0887-6924
Publisher:	Nature Publishing Group
Date Published:	2015-06-01
Start Page:	1290
End Page:	1300
Language:	English
DOI:	10.1038/leu.2015.18
PROVIDER:	scopus
PMCID:	PMC4456293
PUBMED:	25650089
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84930577576&partnerID=40&md5=dcd846b09e619b4744c07e4006c146bc
Notes:	Export Date: 2 July 2015 -- Source: Scopus

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