AML transformation in 56 patients with Ph− MPD in two well defined populations

Abdulkarim, Khadija; Girodon, François; Johansson, Peter; Maynadié, Marc; Kutti, Jack; Carli, Paule‐Marie; Bovet, Emeline; Andréasson, Björn

doi:10.1111/j.1600-0609.2008.01163.x

Cited by 68 publications

(55 citation statements)

References 18 publications

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“…Of note, the leukemic clone appeared to arise from the aberrant MEP population, because this disease compartment was able to induce disease in secondary recipients. It is notable in this regard that acute erythroid leukemia and acute megakaryoblastic leukemia, which are rare immunophenotypic subtypes of de novo AML, often are observed in patients with post-MPN AML (8,30). We hypothesize that post-MPN AML can arise through the acquisition of TP53 mutations by JAK2V617F-mutant MEP cells, which are expanded in chronicphase disease but do not show increased self-renewal until the time of leukemic transformation.…”

Section: Discussionmentioning

confidence: 93%

Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms

Rampal¹,

Ahn²,

Abdel-Wahab³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

246

278

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Patients with myeloproliferative neoplasms (MPNs) are at significant, cumulative risk of leukemic transformation to acute myeloid leukemia (AML), which is associated with adverse clinical outcome and resistance to standard AML therapies. We performed genomic profiling of post-MPN AML samples; these studies demonstrate somatic tumor protein 53 (TP53) mutations are common in JAK2V617F-mutant, post-MPN AML but not in chronic-phase MPN and lead to clonal dominance of JAK2V617F/TP53-mutant leukemic cells. Consistent with these data, expression of JAK2V617F combined with Tp53 loss led to fully penetrant AML in vivo. JAK2V617F-mutant, Tp53-deficient AML was characterized by an expanded megakaryocyte erythroid progenitor population that was able to propagate the disease in secondary recipients. In vitro studies revealed that post-MPN AML cells were sensitive to decitabine, the JAK1/2 inhibitor ruxolitinib, or the heat shock protein 90 inhibitor 8-Treatment with ruxolitinib or PU-H71 improved survival of mice engrafted with JAK2V617F-mutant, Tp53-deficient AML, demonstrating therapeutic efficacy for these targeted therapies and providing a rationale for testing these therapies in post-MPN AML. (1). Mutations in JAK2 have been identified in the majority of patients with PV, ET, and PMF (2-6), underscoring the importance of activated JAK-STAT signaling to the pathogenesis of chronicphase MPN. Despite the increasing use of empiric and targeted therapies, a subset of MPN patients transform to secondary acute myeloid leukemia (AML). Leukemic transformation occurs in 1%, 4%, and 20% of patients over a 10-y period in ET, PV, and PMF, respectively (7). MPN patients who develop leukemic transformation have a dismal outcome, with a median survival of less than 6 mo (8). Advanced age (>60 y) and exposure to chemotherapy increase the risk of leukemic transformation; however, the mechanisms and pathways that contribute to transformation from MPN to AML have not been well delineated. Importantly, the use of standard AML therapies, including induction chemotherapy, has not been shown to improve outcome for patients with post-MPN AML (8, 9). These data indicate a need for new models and improved therapeutic approaches to improve outcomes for patients who have transformed from MPN to AML and to identify genetic lesions associated with leukemic transformation.Genetic studies of paired samples before and after leukemic transformation have suggested there are at least two distinct routes for leukemic transformation. Some patients who present with a JAK2/MPL-positive MPN progress to JAK2/MPL-positive AML that is associated with the acquisition of additional genetic alterations (10-13). A second, more complex route to AML from MPN has been described in which a JAK2/MPL-positive MPN is followed by JAK2/MPL-negative AML (14, 15). Clonality studies using X-chromosome inactivation in informative females demonstrated that JAK2/MPL-positive MPN and JAK2/MPL-negative AML are clonally related, consistent with transformation of an antecedent, preJAK2...

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Section: Discussionmentioning

confidence: 93%

Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms

Rampal¹,

Ahn²,

Abdel-Wahab³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

246

278

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“…1,7,8 Furthermore, patients with certain diseases/syndromes (eg, myeloproliferative neoplasms [MPNs] and Down syndrome) have a propensity to develop AML and MDS. [9][10][11] However, the majority of patients with AML/MDS have no history of any known risk factor.…”

Section: Introductionmentioning

confidence: 99%

Chronic Immune Stimulation Might Act As a Trigger for the Development of Acute Myeloid Leukemia or Myelodysplastic Syndromes

Kristinsson

Björkholm

Hultcrantz

et al. 2011

JCO

253

205

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A B S T R A C T PurposePatients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) often present with infections, but there are little data to assess whether a personal history of selected infections may act as pathogenic triggers. To additionally expand our knowledge on the role of immune stimulation in the causation of AML and MDS, we have conducted a large, population-based study to evaluate the risk of AML and MDS associated with a prior history of a broad range of infections or autoimmune diseases. Patients and MethodsBy using population-based central registries in Sweden, we included 9,219 patients with AML, 1,662 patients with MDS, and 42,878 matched controls. We used logistic regression to calculate odds ratios (ORs) and 95% CIs for the association of AML or MDS with infectious and/or autoimmune diseases. ResultsOverall, a history of any infectious disease was associated with a significantly increased risk of both AML (OR, 1.3; 95% CI, 1.2 to 1.4) and MDS (OR, 1.3; 95% CI, 1.1 to 1.5). These associations were significant even when we limited infections to those occurring 3 or more years before AML/MDS. A previous history of any autoimmune disease was associated with a 1.7-fold (95% CI, 1.5 to 1.9) increased risk for AML and 2.1-fold (95% CI, 1.7 to 2.6) increased risk for MDS. A large range of conditions were each significantly associated with AML and MDS. ConclusionOur novel findings indicate that chronic immune stimulation acts as a trigger for AML/MDS development. The underlying mechanisms may also be due to a common genetic predisposition or an effect of treatment for infections/autoimmune conditions.

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“…The yearly risk for transformation is 0.38%, 0.37%, and 1.09% for PV, ET, and PMF, respectively. 3 The genetic causes of MPN initiation and progression have been studied extensively in the last decades. Numerous reports have been published investigating chromosomal abnormalities using conventional cytogenetic technologies.…”

Section: Introductionmentioning

confidence: 99%

Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression

Klampfl

Harutyunyan

Berg

et al. 2011

Blood

156

147

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AML transformation in 56 patients with Ph− MPD in two well defined populations

Cited by 68 publications

References 18 publications

Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms

Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms

Chronic Immune Stimulation Might Act As a Trigger for the Development of Acute Myeloid Leukemia or Myelodysplastic Syndromes

Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression

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