Lnk inhibits myeloproliferative disorder-associated JAK2 mutant, JAK2V617F

Gery, Sigal; Cao, Qi; Gueller, Saskia; Xing, Hongtao; Tefferi, Ayalew; Koeffler, H. Phillip

doi:10.1189/jlb.0908575

Cited by 72 publications

(69 citation statements)

References 49 publications

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“…However, the role of Lnk in malignant HSPC expansion has not been studied. When overexpressed in cell lines, Lnk inhibits JAK2V617F-mediated proliferation in BaF3 cells (19,20). However, the role of Lnk in hematologic malignancies in vivo had not been examined.…”

Section: Discussionmentioning

confidence: 99%

“…In human MPD patients, Lnk deficiency would be expected to endow JAK2V617F + or BCR/ABL + HSPCs with a growth advantage over progenitors with WT Lnk. So far, Lnk expression levels have been examined in a few cases of human MPD and CML patients, and the results appeared disparate (19,32,38). Therefore, studies measuring Lnk expression in larger cohorts of human MPD patients are required.…”

Section: Discussionmentioning

confidence: 99%

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Lnk constrains myeloproliferative diseases in mice

Bersenev¹,

Wu²,

Balcerek³

et al. 2010

J. Clin. Invest.

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Hematopoietic stem and progenitor cell (HSPC) expansion is regulated by intrinsic signaling pathways activated by cytokines. The intracellular kinase JAK2 plays an essential role in cytokine signaling, and activating mutations in JAK2 are found in a number of hematologic malignancies. We previously demonstrated that lymphocyte adaptor protein (Lnk, also known as Sh2b3) binds JAK2 and attenuates its activity, thereby limiting HSPC expansion. Here we show that loss of Lnk accelerates and exacerbates oncogenic JAK2-induced myeloproliferative diseases (MPDs) in mice. Specifically, Lnk deficiency enhanced cytokine-independent JAK/STAT signaling and augmented the ability of oncogenic JAK2 to expand myeloid progenitors in vitro and in vivo. An activated form of JAK2, unable to bind Lnk, caused greater myeloid expansion than activated JAK2 alone and accelerated myelofibrosis, indicating that Lnk directly inhibits oncogenic JAK2 in constraining MPD development. In addition, Lnk deficiency cooperated with the BCR/ABL oncogene, the product of which does not directly interact with or depend on JAK2 or Lnk, in chronic myeloid leukemia (CML) development, suggesting that Lnk also acts through endogenous pathways to constrain HSPCs. Consistent with this idea, aged Lnk -/-mice spontaneously developed a CML-like MPD. Taken together, our data establish Lnk as a bona fide suppressor of MPD in mice and raise the possibility that Lnk dysfunction contributes to the development of hematologic malignancies in humans.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lnk constrains myeloproliferative diseases in mice

Bersenev¹,

Wu²,

Balcerek³

et al. 2010

J. Clin. Invest.

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“…4 LNK (as in Links) maps to chromosome 12q24.12 and encodes for a membrane-bound adaptor protein that negatively regulates JAK2 signaling. 18 LNK mutations usually involve exon 2, are inactivating, and occur in ϳ10% of patients with blast-phase MPN, whereas they are infrequent in chronic-phase disease. 19 -21 CBL (Casitas B-lineage lymphoma proto-oncogene) maps to chromosome 11q23.3, and its mutations involve exons 8 and 9.…”

Section: Overview Of Mutations Associated With Bcr-abl1-negative Mpnsmentioning

confidence: 99%

Uses and Abuses of JAK2 and MPL Mutation Tests in Myeloproliferative Neoplasms

Tefferi

Noël

Hanson

2011

The Journal of Molecular Diagnostics

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JAK2V617F is sufficiently prevalent in BCR-ABL1-negative myeloproliferative neoplasms (MPNs) to be useful as a clonal marker. JAK2V617F mutation screening is indicated for the evaluation of erythrocytosis, thrombocytosis, splanchnic vein thrombosis, and otherwise unexplained BCR-ABL1-negative granulocytosis. However, the mutation does not provide additional value in the presence of unequivocal morphologic diagnosis, and its presence does not necessarily distinguish one MPN from another or provide useful prognostic information. In general, quantitative cell-based JAK2V617F mutation assays are preferred because the additional information obtained on mutant allele burden enhances diagnostic certainty and facilitates monitoring of response to treatment. JAK2 exon 12 mutation screening is indicated only in the presence of JAK2V617F-negative erythrocytosis that is associated with a subnormal serum erythropoietin level. MPL mutations are neither frequent nor specific enough to warrant their routine use for MPN diagnosis, but they may be useful in resolving specific diagnostic problems. The practice of en bloc screening for JAK2V617F, JAK2 exon 12, and MPL mutations is scientifically irrational and economically irresponsible. Morphology is the cornerstone of current diagnosis and classification in myeloid malignancies. 1 Cytochemical, immunophenotypic, cytogenetic, and molecular data enhance diagnostic accuracy and form the basis for the World Health Organization classification of myeloid malignancies into five main categories 2 : acute myeloid leukemia, myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs), MDS/MPN overlap, and platelet-derived growth factor receptor gene or fibroblast growth factor receptor 1 gene rearranged myeloid/lymphoid neoplasms associated with eosinophilia. The World Health Organization MPN category includes eight subcategories: chronic myelogenous leukemia, polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), mastocytosis, chronic eosinophilic leukemia not otherwise specified, chronic neutrophilic leukemia, and MPN unclassifiable. 1 Among these subcategories, the first four (ie, chronic myelogenous leukemia, PV, ET, and PMF) are currently referred to as "classic" MPNs, because they were included in the original description of myeloproliferative disorders by William Dameshek. 3 In general, current evidence supports consideration of all myeloid malignancies, including MPN, as clonal stem cell diseases.JAK2 and MPL mutations occur across the spectrum of myeloid malignancies, including MPN, MDS, MDS/MPN, and acute myeloid leukemia (Table 1). 4 -7 These mutations are most prevalent in the BCR-ABL1-negative classic MPN (ie, PV, ET, and PMF), which are morphologically characterized by the absence of both cellular dysplasia

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“…7 LNK has been shown to down regulate signaling downstream of MPLW515L and JAK2V617F in vitro. 8,9 Indeed, in a transduction-transplant murine model, LNK deficiency accelerates and exacerbates MPN development induced by TEL-JAK2 and JAK2V617F. 10 In this model, physical interaction between JAK2V617F and LNK was required for the latter's ability to restrain PV/MF expression; similarly LNK's SH2 domain was required for its ability to restrain TEL-JAK2 induced myeloid expansion in this model.…”

Section: Introductionmentioning

confidence: 99%

LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations

et al. 2010

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LNK mutation analysis was performed in 61 patients with blast-phase myeloproliferative neoplasms (MPN); post-primary myelofibrosis (PMF) in 41, post-polycythemia vera in 11 and post-essential thrombocythemia in 9 patients. Paired chronicblast phase sample analysis was possible in 26 cases. Nine novel heterozygous LNK mutations were identified in eight (13%) patients: six exon 2 missense mutations involving codons 215, 220, 223, 229 and 234, a synonymous mutation involving codon 208, and two deletion mutations involving exon 2 (685-691_delGGCCCCG) or exon 5 (955_delA); eight affected the pleckstrin homology (PH) domain. Mutations were detected in six (9.8%) blast-phase samples; chronic-phase sample analysis in four of these revealed the same mutation in one. Mutant LNK was detected in chronic-phase only in two patients and in both chronic-blast phases in one. JAK2V617F was documented in three and IDH2R140Q in one LNK-mutated patients. LNK mutations were not detected in 78 additional patients with chronic-phase MPN enriched for TET2, IDH, JAK2V617F, or MPL-mutated cases. We conclude that LNK mutations (i) target an exon 2 'hot spot' in the PH domain spanning residues E208-D234, (ii) might be more prevalent in blast-phase PMF and (iii) are not mutually exclusive of other MPN-associated mutations but rarely occur in their presence in chronic-phase disease.

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Lnk inhibits myeloproliferative disorder-associated JAK2 mutant, JAK2V617F

Cited by 72 publications

References 49 publications

Lnk constrains myeloproliferative diseases in mice

Lnk constrains myeloproliferative diseases in mice

Uses and Abuses of JAK2 and MPL Mutation Tests in Myeloproliferative Neoplasms

LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations

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