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ORIGINAL ARTICLE  
Year : 2018  |  Volume : 61  |  Issue : 2  |  Page : 209-213
Molecular genetics of BCR-ABL1 negative myeloproliferative neoplasms in India


Tata Memorial Centre, Hematopathology Laboratory, Mumbai, Maharashtra, India

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Date of Web Publication20-Apr-2018
 

   Abstract 


Introduction: Over the past decade, we have moved on from a predominantly morphological and clinical classification of myeloproliferative neoplasms (MPN) to a more evolved classification that accounts for the molecular heterogeneity that is unique to this subgroup of hematological malignancies. This usually incorporates mutations in Janus kinase 2 (JAK2), MPL, and calreticulin (CALR) genes. In this manuscript, we report the frequency of these mutations in a cohort of Indian patients at a tertiary cancer center. Materials and Methods: One hundred and thirty cases of MPN were included in this study. These cases were diagnosed and classified based on the World Health Organization 2008 criteria. JAK2 and MPL mutations were detected using high sensitivity allele-specific polymerase chain reaction using fluorescent labeled primers followed by capillary electrophoresis. A subset of JAK2 and CALR mutations were assessed using a fragment length assay. Results: Among the MPN, we had 20 cases of polycythemia vera (PV), 34 cases of essential thrombocythemia (ET), and 59 of myelofibrosis (MF). JAK2, MPL, and CALR mutations were mutually exclusive of each other. Seventeen cases were categorized as MPN unclassifiable (MPN-U). JAK2p.V617F and MPL mutations were present in 60% (78 of 130) and 5.3% (7 of 130) of all MPN. All the PV cases harbored the JAK2 p.V617F mutation. A total of 23.8% (31 of 130) of patients harbored CALR mutations. CALR exon 9 mutations were detected in 60.8% (14 of 23) and 50% (5 of 10) of JAK2 and MPL negative MF and ET cases, respectively. MPN-U cases included three JAK2 p.V617F positive, two MPL p.W515 L, and 12 CALR positive cases. Ten different types of CALR indels (8 deletions and 2 insertions) were detected of which Type I and Type II mutations were the most common, occurring at a frequency of 45.1% (14 of 31) and 22.5% (7 of 31), respectively. Discussion and Conclusion: We report frequencies of JAK2 p. V617F, MPL exon 10 and CALR mutations in 130 patients similar to those reported in western literature. These mutations carry not only diagnostic but also prognostic relevance.

Keywords: Calreticulin, Janus kinase 2, molecular genetics of myeloproliferative neoplasms in India, MPL

How to cite this article:
Rabade N, Subramanian P G, Kodgule R, Raval G, Joshi S, Chaudhary S, Mascarenhas R, Tembhare P, Gujral S, Patkar N. Molecular genetics of BCR-ABL1 negative myeloproliferative neoplasms in India. Indian J Pathol Microbiol 2018;61:209-13

How to cite this URL:
Rabade N, Subramanian P G, Kodgule R, Raval G, Joshi S, Chaudhary S, Mascarenhas R, Tembhare P, Gujral S, Patkar N. Molecular genetics of BCR-ABL1 negative myeloproliferative neoplasms in India. Indian J Pathol Microbiol [serial online] 2018 [cited 2020 Apr 6];61:209-13. Available from: http://www.ijpmonline.org/text.asp?2018/61/2/209/230541





   Introduction Top


Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell neoplasms characterized using the proliferation of one or more cell lineages of myeloid, erythroid, or megakaryocytic origin. The common BCR-ABL1 negative MPN include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (MF) which result in resulting in increased numbers of erythrocytes, platelets, and/or granulocytes in the peripheral blood along with enlargement of the spleen. The risk of occurrence of complications such as thromboembolic phenomena or the progression to acute myeloid leukemia differs between the types of MPN and hence, reliable differentiation between them is essential. Although bone marrow findings in PV, ET, and MF show some degree of overlap, certain features such as the presence of with loose clusters of giant megakaryocytes (PV), predominant proliferation of hyper lobulated or “staghorn” megakaryocytes without reticulin fibrosis (ET) or megakaryocyte proliferation with marked atypia along with myeloid proliferation and the presence of reticulin fibrosis (MF) are helpful in distinguishing the three subtypes.

Insight into the molecular pathogenesis of these disorders was first provided by the discovery of a single, gain of function, point mutation in the Janus kinase 2 (JAK2) gene in 2005.[1],[2],[3] This mutation predicts an amino acid substitution of valine to phenylalanine at position 617 (p.V617F) in the JH2 pseudokinase domain and leads to constitutive activation of JAK2.[3] The JAK2pV617F mutation is seen in over 95% of the patients of PV and 50%–60% of ET and MF patients.[1],[3]JAK2 exon 12 mutations are seen in 5% of cases of PV only.[4] Point mutations in codon 515 of the thrombopoietin (TPO) receptor gene (MPL) are seen in 5%–10% of cases of JAK2 negative ET and MF.[5]

In addition to JAK2 and MPL, calreticulin (CALR) mutations have now been included as one of the diagnostic criteria in the 2016 update of the World Health Organization (WHO) classification of myeloid neoplasms.[6] Moreover, these mutations have also changed the therapeutic approach from cytoreductive therapy to targeted therapy such as the use JAK2 inhibitor Ruxolitinib. Considering the significant impact of these mutations in the diagnosis, classification and therapy of MPN; we describe the frequency and pattern of mutations in adult Indian patients with MPN.


   Materials and Methods Top


Myeloproliferative neoplasms diagnosis

We retrospectively accrued 130 cases of BCR-ABL1 negative MPN referred to our Institute for detection of JAK2, MPL and CALR mutations over a period of 2 years. Patient records were assessed on the electronic medical records (EMR) for relevant laboratory and clinical information. The diagnosis of MPN was based on the WHO 2008 criteria. Diagnostic samples (bone marrow/peripheral blood) of patients were referred to the hematopathology laboratory, molecular division for molecular testing. Clinical and laboratory characteristics were collected from EMR and laboratory test requisition forms. Wright-stained bone marrow smears and H and E stained trephine biopsies were assessed using hematopathologists. BM fibrosis was assessed according to the WHO 2008 grading system on a scale of MF-0 to MF-3.

DNA extraction

For mutation screening, genomic DNA was extracted from peripheral blood/bone marrow samples using Qiagen Blood mini kit (Qiagen, Germany). DNA quality was checked by NanoDrop 2000 spectrophotometer (Thermo Scientific, USA).

Mutation screening

Each case was subjected to screening for JAK2 p.V617F, CALR, MPL, and JAK2 exon 12 mutations. We used the primer sequences and cycling conditions previously published by various groups for standardizing in-house polymerase chain reaction (PCR)-based assays.

JAK2 p.V617F mutation

The allele-specific PCR assay (assay sensitivity 1%), described by Baxter et al., with fluorescence-labeled primers was used for detection of the JAK2p. V617F mutation.[1] The PCR setup included a common reverse primer, a forward mutation-specific primer (resulting in a 200 base pair product) and a forward “wild-type” specific primer (resulting in a 360 base pair product) which also serves as an internal PCR control.

Calreticulin mutations

Capillary electrophoresis based fragment length analysis assay was optimized for the detection of CALR exon 9 insertions and deletions (indels). PCR setup and primer sequences were as per those described by Klampfl et al.[7]

MPL exon 10 mutations

A two tube allele-specific PCR approach, previously described by Furtado et al.,[8] was used for detection of the common MPL exon 10 mutations (p.W515 L, p.W515K, p.W515A, p.S505N). Each PCR was setup with two primer pairs, which included common forward and reverse primers (forming a 208 bp internal PCR control band) along with forward and reverse mutation-specific primers, respectively.

Janus kinase 2 exon 12 mutations

JAK2 exon 12 mutations were detected using a previously described multiplexed PCR assay,[9] using a combination of allele specific primers (for detection of p.K539 L mutations) and fragment length analysis (for the detection of indels).

The PCR amplicons were diluted with distilled water and further processed for capillary electrophoresis using GeneScan 500 LIZ dye standard (Applied Biosystems, USA) and Hi-Di Formamide (Applied Biosystems, USA). Capillary electrophoresis was performed on the ABI3500 genetic analyzer (Applied Biosystems, USA) and the results were analyzed using peak scanner. A positive control, biological negative control, and a no template control were included with each batch of samples, as internal controls. The JAK2p.V617F is part of the College of American Pathologists (CAP) (ID – 8731530-01) external quality assurance (EQAS) program and has been within acceptable range for the past 3 years. The JAK2p. The V617F assay was validated by both Sanger sequencing, and an amplification refractory mutation system PCR assay as described by Jones et al.[10] CALR and MPL mutations were validated by Sanger sequencing.

Statistical analysis

Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) software (IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY, USA). Chi-square test and Mann-Whitney U-test was used to compare variables and P < 0.05 was considered as statistically significant.


   Results Top


We studied 130 cases of MPN with a median age of 50 years (range 17–83 years) and included 82 males and 48 females (male:female 1.7:1). Constitutional symptoms such as low-grade fever, generalized weakness, weight loss, abdominal pain, and distension were the most common presenting symptoms. Among the MPN, we had 20 cases of PV, 34 cases of ET and 59 of MF. Seven patients presented with past or present history of thrombotic events such as Budd Chiari syndrome, cerebrovascular accidents, portal vein thrombosis, and two additional ones have chronic nonhealing ankle ulcers. Patients with a history of thrombosis included four PV and three ET cases. Notably, all the 7 were JAK2 p.V617F positive. Seventeen cases were categorized as MPN unclassifiable (MPN-U) either due to overlapping features or due to the lack of complete clinical details, especially in cases referred to our institute for mutation detection only. The ET cases had a median hemoglobin level of 13.8 g/dL (range 7.8–16.1 g/dL) and a median platelet count of 830 × 10^9/L (range 450–1754 × 10^9/L). The median hemoglobin and platelet values for MF patients was 9.6 g/dL (range 4.7–17.7 g/dL) and 263 × 10^9/L (range 15–816 × 10^9/L), respectively. The median total white blood cell count was 17.5 × 10^9/L (range 1.5–50.9 × 10^9/L). Laboratory findings are detailed in [Table 1].
Table 1: Laboratory findings of myeloproliferative neoplasms patients

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JAK2, MPL, and CALR mutations were mutually exclusive of each other. The distribution of mutations in MPN is detailed in [Table 2]. JAK2p.V617F and MPL mutations were present in 60% (78 of 130) and 5.3% (7 of 130) of all MPN. All the PV cases were JAK2 p.V617F positive. JAK2 exon12 mutation was not detected in any case. A total of 23.8% (31 of 130) of patients (21 males and 10 females) with a median age of 46 years (range 21–60 years) harbored CALR mutations. CALR exon 9 mutations were detected in 60.8% (14 of 23) and 50% (5 of 10) of JAK2 and MPL negative MF and ET cases, respectively. [Table 3] and [Table 4] outline the characteristics of MF and ET patients according to their mutation profiles. The MPN-U category included three JAK2 p.V617F positive, two MPL p.W515 L, and 12 CALR positive cases. We found no statistically significant difference in the median hemoglobin, platelet or total white cell count values between the JAK2, CALR mutated, and triple negative subgroups within patients with ET and MF.
Table 2: Distribution of mutations in myeloproliferative neoplasms

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Table 3: Characteristics of myelofibrosis patients according to their mutation profiles

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Table 4: Characteristics of essential thrombocythemia patients according to their mutation profiles

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Ten different types of CALR indels (8 deletions and 2 insertions) were detected of which Type I and Type II mutations were the most common, occurring at a frequency of 45.1% (14 of 31) and 22.5% (7 of 31), respectively. Eight of the 14 (57.1%) CALR positive MF cases had Type I, whereas 3 (21.4%) had Type II mutations. Two of the 5 (40%) CALR mutations in ET were Type I and only one showed Type II mutation. Approximately 15% of the ET and MF patients were classified as triple-negative (nonmutated JAK2, CALR, and MPL).

One case with co-occurrence of BCR-ABL1 and JAK2 p.V617F was also present in our study. This patient was evaluated for JAK2 p.V617F mutation due to persistent thrombocytosis (platelet count >630 × 10^9/L) and mild splenomegaly (3 cm below costal margin) after achieving complete cytogenetic remission at 6 months. The patient had a BCR-ABL1 international scale normalized copy number (IS NCN) of 0.805%, after 14 months of imatinib therapy, at the time point of JAK2 p.V617F mutation detection. He achieved major molecular response after 18 months of therapy (IS NCN - 0.028%) and is currently asymptomatic with a platelet count of 541 × 10^9/L.


   Discussion Top


With the discovery of JAK2, MPL and CALR mutations we now have a better understanding of the pathogenesis and a definitive molecular diagnosis for the classical BCR-ABL1 negative MPN. Apart from diagnosis, these mutations also have implications for targeted therapy and prognostic relevance. In our study, the JAK2 p.V617F mutation was detected in 100%, 57.6% and 61.7% of cases of PV, MF, and ET, respectively [Table 1]. The frequency of mutations in this study is similar to published data.[1],[4],[11] The 100% frequency of JAK2 positivity in PV could be due to the relatively small number of patients. Another Indian study found a similar frequency of JAK2 mutation in MF (52%) but higher in ET (70%) as compared to our results.[12] We found seven cases with mutations at codon 515 of the MPL gene. These included four p.W515 L and three p.W515K variants. TPO – MPL signaling is essential for hematopoietic stem cell survival and activation in addition to being the primary regulator of megakaryopoiesis. Mutations in MPL were first reported by Pikman Y et al. in up to 9% of patients with JAK2 negative MF.[5] Further studies reported an occurrence of point mutations at codon 515 in up to 5% cases of ET.[4],[11] The findings in our study are in concordance with those previously reported.

In spite of the discovery of JAK2 and MPL mutations, molecular pathogenesis in almost one-third of ET and MF cases remained obscure. In 2013, two groups (Nangalia et al. and Klampfl et al.) described the presence of somatic mutations in the CALR gene in patients with JAK2 and MPL negative ET and MF. All the mutations described to localize to exon 9 of the CALR gene and led to the formation of a mutant protein with negatively charged amino acids at the C terminal end.[13] Although over 30 types of indels have been described, Types 1 (52-bp deletion [p.L367fs*46]) and 2 (5-bp insertion [p.K385fs*47]) are the most common.[7],[14] Recently, insights into the pathogenesis of mutant CALR were provided by Marty et al. and Pietra et al. Mutant CALR acts through abnormal MPL signaling leading to constitutive activation of JAK/STAT pathway.[15] The Type 1 mutation is reported to be associated with an MF phenotype, whereas the type 2 is generally associated with ET.[13],[16]

Apart from the diagnostic importance, the presence of CALR mutation was found to be associated with higher platelet counts, lower risk of thrombosis as well as leukemic transformation as compared to their JAK2 mutated counterparts.[7],[14] Even within CALR positive cases of MF, Type I mutations have better overall survival rates.[17] The discovery of CALR mutations has led to a change in the diagnostic algorithm of MPN. We found that 23.8% patients harbored CALR indels, with a frequency of 50% and 60.8% in JAK2 and MPL negative ET and MF, respectively. The data are similar to that published by Tefferi et al. (32%) but significantly lower than that of Rotunno et al. (48.9%), Qiao et al. (57%), Klampfl et al. (67%) and as a consequence the number or patients included in the triple negative MPN category in our study was higher than that reported by these groups.[7],[11],[18],[19] When compared to Klampfl et al. (88%), we also had a significantly lower frequency CALR mutation in patients with MF. Patients with CALR mutated ET have been reported to have lower hemoglobin level, lower total leukocyte counts, and higher platelet counts as compared to JAK2 mutated cases. Similar findings have also been reported in cases with MF.[7] However, our data failed to reveal any statistically significant difference in these parameters in ET and MF cases.

A previously published study on 70 Indian patients described 11% CALR mutated cases but include only Type I.[20] Although we found 10 different types of mutations, Types I and II were the most common present in 45.1% and 22.5% of cases, respectively. The frequency of occurrence of 52 bp deletion within exon 9 of CALR is in concordance, but that of 5 bp insertion is somewhat lower than that reported by Klampfl et al. (53% and 31%), Nangalia et al. (45% and 41%) and Qiao et al. (44.6% and 33.8%).[7],[14],[18] The p.L367fs*46 mutation was commonly associated with MF in our study, but we did not find any association of p.K385fs*47 mutations with ET cases as per literature. Type 1 mutations have been described in 75% MF and 48% ET cases which is much higher than our study (57.1% and 40%, respectively).[16],[17] However, Type II mutations occurred at a similar frequency of approximately 20%, as compared to previously published data.[7]

Interestingly, we also report a case with co-occurrence of BCR-ABL1 and JAK2 mutation. The long believed notion of the mutually exclusive nature of BCR-ABL1 and JAK2p.V617F mutation has been challenged over the past few years. Although this co-occurrence is rare, short case series and isolated case reports have reported this phenomenon.[21],[22],[23],[24] Phenotypic expression of the JAK2 mutation in these reported cases may vary, but progression to MF is the most frequently reported. However, one of the features commonly observed in these cases is the retrospective detection of the JAK2 mutation at the time of initial diagnosis of chronic myeloid leukemia (CML). These findings indicate that JAK2p.V617F mutation may precede the acquisition of BCR-ABL translocation or co-occurs with it.[24] Development of two independent clones with BCR-ABL1 and JAK2 or the emergence of a sub clone, are the two hypothesis proposed to explain this co-occurrence.[21],[22],[23],[24] Pastore et al. also report a case with persistent thrombocytosis in a patient of CML on dasatinib. The author describes a case in which a predominant BCR-ABL clone successfully reduced following treatment and ultimately unmasked features attributable to JAK2p.V617F-positive ET.[25]


   Conclusion Top


We report JAK2, MPL and CALR mutations occurring in Philadelphia chromosome negative MPN with frequencies similar to those in western literature but higher frequencies of CALR mutations in MPN than previously reported in India. The study is possibly one of the first to report MPL mutations from India.

Acknowledgment

Dr Nikhil Patkar is supported by the wellcome trust-DBT/India Alliance through an intermediate Fellowship for Clinicians and Public Health Researchers.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 2006;3:e270.  Back to cited text no. 5
    
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[PUBMED]  [Full text]  
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Pastore F, Schneider S, Christ O, Hiddemann W, Spiekermann K. Impressive thrombocytosis evolving in a patient with a BCR-ABL positive CML in major molecular response during dasatinib treatment unmasks an additional JAK2V617F. Exp Hematol Oncol 2013;2:24.  Back to cited text no. 25
    

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Correspondence Address:
Nikhil Rabade
Tata Memorial Centre, Hematopathology Laboratory, Ground Floor, CCE Building, ACTREC, Mumbai - 410 210, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJPM.IJPM_223_17

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]

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Ranjan Agrawal
Indian Journal of Pathology and Microbiology. 2018; 61(2): 169
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