scholarly journals JAK2 V617F-Positive Acute Myeloid Leukemia: Clinicopathological Features of Two Cases

2022 ◽  
Vol 12 (1) ◽  
pp. 53-57
Author(s):  
Youngeun Lee ◽  
Ji Yun Lee ◽  
Jeong-Ok Lee ◽  
Soo-Mee Bang ◽  
Sang Mee Hwang
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Jak2 V617f ◽  
Clinicopathological Features ◽  
Acute Myeloid

scholarly journals JAK2 V617F-Mutated Myeloproliferative Neoplasia Developing Five Years after Wild-Type JAK2 Acute Myeloid Leukemia: A Case Report

2013 ◽  
Vol 129 (1) ◽  
pp. 23-25 ◽  
Author(s):  
Sabine Girsberger ◽  
Axel Karow ◽  
Pontus Lundberg ◽  
Stephan Dirnhofer ◽  
Thomas Lehmann ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Case Report ◽  
Myeloid Leukemia ◽  
Jak2 V617f ◽  
Wild Type ◽  
Acute Myeloid

Clinical Characteristics of JAK2 V617F Mutation Positive Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4508-4508
Author(s):  
Sarolta Nahajevszky ◽  
Hajnalka Andrikovics ◽  
Zoltan Matrai ◽  
Nora Lovas ◽  
Sandor Lueff ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clinical Characteristics ◽  
De Novo ◽  
Age Of Onset ◽  
Jak2 V617f ◽  
Blastic Transformation ◽  
V617f Mutation ◽  
Acute Myeloid ◽  
Time Point

Abstract Chronic myeloproliferative diseases (CMPD) are clonal disorders of pluripotent hematopoietic stem cells. Acquired JAK2 V617F point mutation has recently been identified as disease causing activating genetic abnormality in classic BCR-ABL negative CMPD (80% of polycythemia vera, 35% of essential thrombocythemia and 50% of chronic idiopathic myelofibrosis cases). JAK2 V617F is rare in other myeloid stem cell disorders like acute myeloid leukemia, chronic myelomonocyter leukemia or myelodysplasia with reported frequency of 3–8%. Between January 2001 and December 2005 155 consecutive adult patients [87 females and 68 males, median age of onset was 49±14 (range 18–83) years] were diagnosed with AML in our institute. Peripheral blood or bone marrow samples drawn at the time point of diagnosis were analyzed for the presence of JAK2 V617F by allele-specific PCR. JAK2 V617F mutation was present in 5 patients (3 males and 2 females; 3.2%). 3 of the 5 patients had prior history of CMPD, while 2 patients were diagnosed with de novo AML. The clinical characteristics and laboratory features of JAK2 V617F positive patients are shown in Table 1. FLT3 internal tandem duplication, FLT3 tyrosine kinase domain mutations, AML1-ETO, CBFB-MYH, PML-RARA rearrangements or nucleophosmin mutations were not present at the time point of AML diagnosis. In the case of patient 1, thrombocytosis was present prior the diagnosis of AML, and bone marrow biopsy revealed grade 3 fibrosis at diagnosis of AML, suggesting the presence of an atypical CMPD with the coexistence of del(5q) MDS. Patient 2 had no remarkable disease in his previous medical history. Induction therapy resulted in complete hematological and cytogenetic remission with persistent JAK2 V617F positivity. 10 month later clinical features of CMPD (elevated white blood cell count, left shifted peripheral blood smear, hepatosplenomegaly) appeared. In conclusion, these two cases suggest that acute myeloid leukemia with JAK-2 V617F mutation in fact corresponds to the blastic transformation of a clinically atipical chronic myeloproliferative disorders. Clinical characteristics and laboratory features of JAK2 V617F positive patients Case Sex AML subtype Age of onset (years) FAB subtype Cytogenetic abnormality Therapy Overall Survival (months) 1 F de novo 52 M1 del(5q) DNR+ara-C, HDara-C 23 2 M de novo 65 M4 t(13;17) DNR+ara-C, HDara-C 12 3 F CMPD blastic transformation 65 M4 trisomy (1q) Supportive 18 4 M CMPD blastic transformation 70 M4 not available Supportive 3 5 M CMPD blastic transformation 71 M4 not available Supportive 6

scholarly journals Protracted Clonal Trajectory of a JAK2 V617F-Positive Myeloproliferative Neoplasm Developing during Long-Term Remission from Acute Myeloid Leukemia

2018 ◽  
Vol 2018 ◽  
pp. 1-4
Author(s):  
Stephen E. Langabeer ◽  
Karl Haslam ◽  
Maria Anne Smyth ◽  
John Quinn ◽  
Philip T. Murphy
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Jak2 V617f ◽  
Time Frame ◽  
Divergent Evolution ◽  
Common Precursor ◽  
Previously Treated ◽  
Acute Myeloid

Although transformation of the myeloproliferative neoplasms (MPNs) to acute myeloid leukemia (AML) is well documented, development of an MPN in patients previously treated for, and in remission from, AML is exceedingly rare. A case is described in which a patient was successfully treated for AML and in whom a JAK2 V617F-positive MPN was diagnosed after seven years in remission. Retrospective evaluation of the JAK2 V617F detected a low allele burden at AML diagnosis and following one course of induction chemotherapy. This putative chemoresistant clone subsequently expanded over the intervening seven years, resulting in a hematologically overt MPN. As AML relapse has not occurred, the MPN may have arose in a separate initiating cell from that of the AML. Alternatively, both malignancies possibly evolved from a common precursor defined by a predisposition mutation with divergent evolution into MPN through acquisition of the JAK2 V617F and AML through acquisition of different mutations. This case emphasizes the protracted time frame from acquisition of a disease-driving mutation to overt MPN and further underscores the clonal complexity in MPN evolution.

Acute Myeloid Leukemia (AML) with t(6;9)(p23;q34) Defines a Very Poor Risk Leukemia Subgroup with Distinguishing Clinicopathological Features: A United States (US) Cytogenetics Intergroup Study of 62 AML and MDS Cases.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 567-567
Author(s):  
Marilyn L. Slovak ◽  
Clara D. Bloomfield ◽  
Holly Gundacker ◽  
Gordon Dewald ◽  
Frederick R. Appelbaum ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Fusion Gene ◽  
Young Patients ◽  
Disease Free Survival ◽  
Clinicopathological Features ◽  
Published Data ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract The t(6;9)(p23;q34) translocation, which results in the formation of a chimeric fusion gene DEK/CAN on the der(6) chromosome, is a rare recurring cytogenetic aberration reported in patients (pts) with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Because the abnormality is an infrequent finding in AML with most reports describing 2 to 8 cases, the US Intergroup Cytogenetics Consortium investigated the frequency and clinical, pathologic and cytogenetic characteristics of t(6;9) leukemia among pts registered to 19 different treatment protocols. Among 6567 pts with evaluable karyotypes, 62 (0.9%) had t(6;9): 30 on pediatric trials (mean 12 yrs; 15/15 male/female) and 32 on adult trials (mean 38 yrs; 21/11 male/female), compared to the mean age of 8 yrs for pts on pediatric AML/MDS trials and 54 yrs for pts on adult AML/MDS trials. Three cases (5%) showed a complex (3- or 4-way) variant translocation and only 7 (11%) of the 62 pts showed secondary aberrations: 3 (10%) of 30 pediatric cases and 4 (13%) of 32 of the adult cases. The majority of t(6;9) cases were classified as FAB-M2 (34%), M4 (31%) or M1 (19%). Although the immunophenotyping (N=7) and morphology data (N=17) were limited, increased basophilia and Auer rods were observed and the blasts showed CD13, CD15, and CD33 expression, in agreement with a previously reported preliminary study (Am J Clin Pathol107:430–437,1997). Four pts (1 pediatric and 3 adults) had MDS. Among the remaining 58 pts, 25 (78%) adults had previously untreated AML (16 de novo, 2 secondary, and 7 unknown secondary/de novo status) while all 29 pediatric AML patients had de novo AML. For the 54 patients with previously untreated AML, complete remission rates were slightly higher, but not statistically significantly (p=.20) in children (69%), when compared to adults (52%). Disease-free survival (DFS) (combined median 8.8 mo, 95% CI, 5.1–13.7) and overall survival (OS) (combined median 11.9 mo, 95% CI, 10.0–14.3) were poor regardless of age, a finding in distinct contrast to the t(8:21) favorable risk group also commonly observed in M2/M4 AML. Kaplan-Meier estimates of 3-yr survival were 25% for pediatric cases and 9% for adults. Analysis of stem cell transplantation (SCT) was inconclusive due to the small number of transplanted patients (N=15), but suggested that allogeneic SCT might be associated with better OS than no SCT (hazard ratio [HR] 0.39 after SCT, 95% CI 0.14 – 1.11), while autologous SCT might not (HR 1.49, 95% CI 0.57–3.85). Based on this study of t(6;9), largest to date and previously published data, AML with t(6;9) leukemia is a distinct AML subgroup with distinguishing clinicopathological features including poor outcome in relatively young patients, not explained by other known poor prognostic factors that warrants novel therapeutic strategies. Similar to other recurring cytogenetic abnormality subtypes of de novo acute myeloid leukemia of the WHO classification, t(6;9) may warrant a specific leukemia disease subtype.

Secondary genetic lesions in acute myeloid leukemia with inv(16) or t(16;16): a study of the German-Austrian AML Study Group (AMLSG)

Blood ◽  
2013 ◽  
Vol 121 (1) ◽  
pp. 170-177 ◽  
Author(s):  
Peter Paschka ◽  
Juan Du ◽  
Richard F. Schlenk ◽  
Verena I. Gaidzik ◽  
Lars Bullinger ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Chromosomal Aberrations ◽  
Myeloid Leukemia ◽  
Jak2 V617f ◽  
Tyrosine Kinase Domain ◽  
Age Difference ◽  
Trisomy 8 ◽  
Kit Mutation ◽  
The Impact ◽  
Acute Myeloid

Abstract In this study, we evaluated the impact of secondary genetic lesions in acute myeloid leukemia (AML) with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11. We studied 176 patients, all enrolled on prospective treatment trials, for secondary chromosomal aberrations and mutations in N-/KRAS, KIT, FLT3, and JAK2 (V617F) genes. Most frequent chromosomal aberrations were trisomy 22 (18%) and trisomy 8 (16%). Overall, 84% of patients harbored at least 1 gene mutation, with RAS being affected in 53% (45% NRAS; 13% KRAS) of the cases, followed by KIT (37%) and FLT3 (17%; FLT3-TKD [14%], FLT3-ITD [5%]). None of the secondary genetic lesions influenced achievement of complete remission. In multivariable analyses, KIT mutation (hazard ratio [HR] = 1.67; P = .04], log10(WBC) (HR = 1.33; P = .02), and trisomy 22 (HR = 0.54; P = .08) were relevant factors for relapse-free survival; for overall survival, FLT3 mutation (HR = 2.56; P = .006), trisomy 22 (HR = 0.45; P = .07), trisomy 8 (HR = 2.26; P = .02), age (difference of 10 years, HR = 1.46; P = .01), and therapy-related AML (HR = 2.13; P = .14) revealed as prognostic factors. The adverse effects of KIT and FLT3 mutations were mainly attributed to exon 8 and tyrosine kinase domain mutations, respectively. Our large study emphasizes the impact of both secondary chromosomal aberrations as well as gene mutations for outcome in AML with inv(16)/t (16;16).

Mass Cytometry Analysis Of Myelofibrosis and Secondary Acute Myeloid Leukemia Reveals Constitutive and Cytokine Induced Signaling Abnormalities With Differential Sensitivities To Ruxolitinib

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1610-1610
Author(s):  
Daniel A.C. Fisher ◽  
Gregory K. Behbehani ◽  
Garry P. Nolan ◽  
Sean C. Bendall ◽  
Stephen T. Oh
Keyword(s):  
Acute Myeloid Leukemia ◽  
Single Cell ◽  
Myeloid Leukemia ◽  
Ex Vivo ◽  
Jak2 V617f ◽  
Signaling Molecules ◽  
Mass Cytometry ◽  
Secondary Acute Myeloid Leukemia ◽  
Acute Myeloid

Abstract The classic myeloproliferative neoplasms (MPNs), including primary and secondary myelofibrosis (MF), are frequently associated with the JAK2 V617F mutation or other genetic alterations in members of the JAK-STAT axis. These mutations induce hyperactivated JAK-STAT signaling in cell lines and mouse models. Other mutations have been found recurrently in human MPNs, however, including mutations associated with transformation of chronic MPNs to secondary acute myeloid leukemia (sAML). The aggregate effects of these mutations on in vivo myeloproliferative signaling and disease phenotypes are not yet well understood. While targeted inhibitors of JAK2 have shown activity in MPNs, evidence of a selective effect on the underlying malignant clone has been lacking. These findings suggest that dysregulation of other signaling molecules may be important in MPN pathogenesis, and that therapeutic targeting of these molecules could be beneficial. Therefore, a more complete assessment of JAK-STAT and related signaling pathways in MPNs is needed. Mass cytometry is a novel technology that merges flow cytometry with mass spectrometry and enables the simultaneous measurement of 30+ parameters at the single cell level. We utilized this approach to examine bone marrow or peripheral blood samples from four MF patients and five sAML patients, as well as three normal controls. Cells were exposed to five different perturbation conditions ex vivo, including the cytokines thrombopoietin (TPO) and G-CSF, and/or the JAK1/2 inhibitor ruxolitinib. Cells were stained with a panel of 18 surface markers and 16 intracellular signaling effectors and analyzed on a CyTOF mass cytometer. Single cell data was analyzed using traditional gating strategies, as well as with SPADE (spanning-tree analysis of density-normalized events), which distills multidimensional data down to interconnected cell subsets based on shared surface marker expression. These methods grouped cells into distinct cell populations including hematopoietic stem/progenitors (HSPCs) and myeloid and lymphoid lineage subsets. Heat maps were constructed to depict basal and induced activation of each intracellular marker. MF and sAML patient samples exhibited abnormal cytokine-induced signaling that varied in a patient-specific manner. HSPC responses to TPO ranged from hyposensitive to hypersensitive compared with normal. Markedly abnormal basal (unstimulated) signaling in the HSPC compartment was observed in all MF and sAML patients. Each sample exhibited increased total IkBα and/or pCREB, typically accompanied by elevated phosphorylation of one or more additional signaling molecules. Both basal elevation and cytokine hypersensitivity were frequently observed within a MAP kinase signaling axis represented by pERK and downstream targets pCREB and pS6. Conversely, repressed basal STAT1 phosphorylation was observed in all patients. These abnormalities were not exclusive to sAML versus MF, nor specific to patients with or without the JAK2 V617F mutation. Widespread dysregulation of total IkBα, pERK-pCREB-pS6, and pSTAT1 suggest that these signaling effectors may be characteristic of a general myeloproliferative signaling phenotype. Ex vivo ruxolitinib effectively inhibited the majority of observed hypersensitive cytokine-stimulated signaling effects. In contrast, most basal signaling elevations were insensitive to ruxolitinib. The signaling molecules most frequently insensitive to ruxolitinib were those most frequently basally elevated in MF and sAML HSPC, namely pCREB and total IkBα. In contrast, phosphorylation of the JAK2 substrates STAT3 and STAT5 was almost always sensitive to ruxolitinib. These results suggest that targeting of myeloproliferative signaling pathways either downstream or independent of JAK2 activity may be valuable for improved treatment of MF and sAML patients. Ongoing experiments are focused on determining whether constitutive ruxolitinib-insensitive signaling abnormalities can be identified in patients treated with ruxolitinib in vivo, which may underlie the incomplete responses observed clinically. Taken together, these approaches will provide a deeper understanding of altered signaling networks in the context of targeted therapies in MPNs. Disclosures: Oh: Incyte: Consultancy, Research Funding, Speakers Bureau.

Sign in / Sign up

Export Citation Format

Share Document