Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice promote disease progression in myeloproliferative neoplasms

Chen, Edwin; Schneider, Rebekka K.; Breyfogle, Lawrence J.; Rosen, Evan B.; Poveromo, Luke; Elf, Shannon; Ko, Amy; Brumme, Kristina; Levine, Ross L.; Ebert, Benjamin L.; Mullally, Ann

doi:10.1182/blood-2014-04-567024

Cited by 90 publications

(91 citation statements)

References 42 publications

(55 reference statements)

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“…Overall changes were subtle and Tet2 loss led mainly to an increased self-renewal signature. 1 In the model of Kameda et al, 2 Jak2V617F decreased this self-renewal signature, and the combined loss of Tet2 only partially restored it, in agreement with what they observed in their mouse model. The precise mechanism by which TET2 loss increases self-renewal capacities of HSCs is still poorly known.…”

Section: William Vainchenker and Isabelle Plo Institut De Cancérologisupporting

confidence: 79%

“…In about 6% of those cases, mutations in the TET2 gene are found even in the absence of any hematologic disorder, demonstrating that TET2 mutations are capable of giving rise to a clonal hematopoiesis, possibly favoring secondarily the occurrence of the JAK2V617F mutation. 9 In the 2 present studies, the authors directly demonstrate that TET2 loss is capable of completely 1 However, the effects of Tet2 loss were not restricted to HSCs but also led to a more severe MPN in mice and accelerated death compared to the single Jak2V617F mutation in the absence of leukemia occurrence. One of the most striking differences is the increased extramedullary hematopoiesis as revealed by a massive splenomegaly in the double-mutant mice.…”

Section: William Vainchenker and Isabelle Plo Institut De Cancérologimentioning

confidence: 50%

“…knockin, which induces a polycythemialike disorder 1 ; that of Kameda et al is a constitutive transgenic Jak2V617F mouse model that leads to a lethal myelofibrosis after transplantation. 2 The reasons for these differences among models are presently unclear, but the level of JAK2V617F expression is the principal determinant in the phenotype, even if the origin (human or murine) of JAK2V617F may also play a role.…”

Section: William Vainchenker and Isabelle Plo Institut De Cancérologimentioning

confidence: 99%

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TET2 loss, a rescue of JAK2V617F HSCs

Vainchenker

Plo

2015

Blood

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Section: William Vainchenker and Isabelle Plo Institut De Cancérologisupporting

confidence: 79%

Section: William Vainchenker and Isabelle Plo Institut De Cancérologimentioning

confidence: 50%

Section: William Vainchenker and Isabelle Plo Institut De Cancérologimentioning

confidence: 99%

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TET2 loss, a rescue of JAK2V617F HSCs

Vainchenker

Plo

2015

Blood

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“…The pathogenetic role of these other mutations is incompletely understood and might include cooperation with the driver mutations in facilitating disease progression [49,50]. Specific genes affected in this regard include those relevant to epigenetic (e.g., ASXL1, TET2, EZH2, IDH1, IDH2, DNMT3A), RNA splicing (e.g., SRSF2, U2AF1, SF3B1) or transcriptional (TP53, IKZF1, NF-E2, CUX1) regulation.…”

Section: Pathogenetic Contribution Of Mutations In Myeloproliferativementioning

confidence: 99%

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

2015

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Myeloproliferative neoplasms (MPN) are clonal stem cell diseases, first conceptualized in 1951 by William Dameshek, and historically included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In 1960, Nowell and Hungerford discovered an invariable association between the Philadelphia chromosome (subsequently shown to harbor the causal BCR‐ABL1 mutation) and CML; accordingly, the term MPN is primarily reserved for PV, ET, and PMF, although it includes other related clinicopathologic entities, according to the World Health Organization (WHO) classification system. In 2005, William Vainchenker and others described a Janus kinase 2 mutation (JAK2V617F) in MPN and this was followed by a series of additional descriptions of mutations that directly or indirectly activate JAK‐STAT: JAK2 exon 12, myeloproliferative leukemia virus oncogene (MPL) and calreticulin (CALR) mutations. The discovery of these, mostly mutually exclusive, “driver” mutations has contributed to revisions of the WHO diagnostic criteria and risk stratification in MPN. Mutations other than JAK2, CALR and MPL have also been described in MPN and shown to provide additional prognostic information. From the standpoint of treatment, over the last 50 years, Louis Wasserman from the Unites States and Tiziano Barbui from Italy had skillfully organized and led a number of important clinical trials, whose results form the basis for current treatment strategies in MPN. More recently, allogeneic stem cell transplant, as a potentially curative treatment modality, and JAK inhibitors, as palliative drugs, have been added to the overall therapeutic armamentarium in myelofibrosis. In the current review, I will summarize the important advances made in the last 10 years regarding the science and practice of MPN. Am. J. Hematol. 91:50–58, 2016. © 2015 Wiley Periodicals, Inc.

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“…In addition, combined Tet2 loss with AML1-ETO leads to fully penetrant AML in vivo, partially due to hypermethylation of enhancer regions thereby silencing tumor suppressors [59,75]. Furthermore, studies from two independent groups have shown that combination of Tet2 loss and Jak2V617F resulted in aggressive MPN phenotype through both clonal HSC dominance and expansion of downstream precursor populations [76,77]. Notably, TET2 mutations also cooccur with changes in other TET members or DNMT3A mutations in human acute B-lymphocytic leukemia and T-cell lymphoma [78,79].…”

Section: Tet2mentioning

confidence: 99%