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Table of Contents
Year : 2022  |  Volume : 2  |  Issue : 2  |  Page : 143-145

Acute myeloid leukemia with nucleophosmin 1 mutation: Clonal hematopoiesis with indeterminate potential or oncogenic potential?

1 Department of Molecular Pathology and Genomics, Kokilaben Dhirubhai Ambani Hospital, Mumbai, Maharashtra, India
2 Department of Hematopathology, Kokilaben Dhirubhai Ambani Hospital, Mumbai, Maharashtra, India
3 Department of Quality Assurance, Kokilaben Dhirubhai Ambani Hospital, Mumbai, Maharashtra, India
4 Department of Laboratory Medicine, Kokilaben Dhirubhai Ambani Hospital, Mumbai, Maharashtra, India
5 Department of Hematology, Kokilaben Dhirubhai Ambani Hospital, Mumbai, Maharashtra, India

Date of Submission19-Oct-2022
Date of Decision12-Nov-2022
Date of Acceptance23-Nov-2022
Date of Web Publication06-Feb-2023

Correspondence Address:
Dr. Amrit Kaur Kaler
Department of Genetics and Molecular Medicine, Kokilaben Dhirubhai Ambani Hospital, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpo.jpo_20_22

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How to cite this article:
Kaler AK, Rabade N, Ghodke K, Tiwarekar Y, Umarji S, Gadgi K, Nikam A, Rane S, Singhal S, Vadera V, Tulpule S. Acute myeloid leukemia with nucleophosmin 1 mutation: Clonal hematopoiesis with indeterminate potential or oncogenic potential?. J Precis Oncol 2022;2:143-5

How to cite this URL:
Kaler AK, Rabade N, Ghodke K, Tiwarekar Y, Umarji S, Gadgi K, Nikam A, Rane S, Singhal S, Vadera V, Tulpule S. Acute myeloid leukemia with nucleophosmin 1 mutation: Clonal hematopoiesis with indeterminate potential or oncogenic potential?. J Precis Oncol [serial online] 2022 [cited 2023 Mar 28];2:143-5. Available from: https://www.jprecisiononcology.com//text.asp?2022/2/2/143/369216

A 43-year-old female, presented with fever, abdominal pain, and weakness in the hematology outpatient department. On physical examination, abdominal tenderness, splenomegaly, and hepatomegaly were noted. The complete blood count showed hyperleukocytosis (total leukocyte count – 1, 3, and 9 × 10^3/l) and thrombocytopenia (63,000/ul). Peripheral smear revealed 44% blasts with no  Auer rods More Details. Bone marrow aspirate showed hypercellular marrow, suppressed trilineage hematopoiesis, and increase in blasts (72%). Cytochemical staining for Myeloperoxidase (MPO) was negative.

Flow cytometric immunophenotyping on peripheral smear revealed acute myeloid leukemia (AML) with monocytic differentiation. The cells express heterogeneous CD13, CD14, CD36, CD38, CD56, and CD123, and moderate CD33, CD34, CD45, CD86, CD4, CD117, and human leukocyte antigen - DR (HLA-DR) markers. Cytogenetic studies showed normal karyotype. Molecular studies revealed the presence of 4-base pairs (bp) insertion (TCTG) on exon 12 in nucleophosphomin1 (NM_002520.7) by fragment analysis; and a heterozygous single-nucleotide variation (SNV) at Fms like Tyrosine Kinase domain (TKD) c.2503G>T p.D835Y (NM_004119.3) by Sanger sequencing [Figure 1] and [Figure 2]. Morphological, immunophenotyping, and molecular findings were consistent with AML with NPM1 mutation. The next-generation sequencing (NGS) done simultaneously showed additional mutations Wilms tumor (WT1) c. 1142_1143insTTGTACGGTC (NM_024426.6) at exon 11 and a SNV in isocitrate dehydrogenase 2 (IDH2) c.419G>A gene at exon 4 (NM_002168.4). The patient was treated with 7 + 3 induction chemotherapy (idarubicin 12 mg/m2 and cytarabine 100 mg/m2 continuous IV infusion) and responded well. Later, midostaurin was added to the treatment regimen based on NGS report.
Figure 1: Sanger sequencing: A heterozygous SNV noted at FTL3 gene at codon D835 in exon 20. SNV: Single nucleotide variation

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Figure 2: Fragment analysis: 4-bp insertion noted in exon 12 of NPM1 gene

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  Discussion Top

AML with NPM1 mutation is a distinct entity defined in the 2017 WHO update and shows favorable prognosis following conventional and consolidation chemotherapy.[1] The recent technologies like NGS have been used to diagnose and measure molecular residual disease after therapy by identifying mutations like NPM1, etc.[2] Certain persistent preleukemic age-related aberrations also known as clonal hematopoiesis of indeterminate potential (CHIP) mutations are clonally stable and indicative of good prognosis such as TET2, DNMT3A, ASXL1, IDH1, IDH2, and SRSF2.[3] Clonal hematopoiesis of potentially oncogenic (CHOP) mutations are disease related trigger the proliferation of neoplastic cells in the molecular background of CHIP mutations such as FLT3, RUNX1, WT1, NPM1, NRAS, and TP53.[3] However, these CHOP mutations in AML like are mostly detected in the context of a full-blown AML and they are not identified in a prediagnostic phase.

The present patient had oncogenic driver mutations (CHOP) in NPM1, FLT3, and WT1. AML with NPM1 mutations accounts for ~30% of adult AML with normal karyotype. It has female preponderance and is less frequent in children. Bone marrow is usually hypercellular and shows multilineage dysplasia in 23% of cases with a strong association with myelomonocytic (FAB M4) and monocytic categories (FAB M5) with a low/nil expression of CD34 and HLA-DR on immunophenotyping. NPM1 gene is located on chromosome 5q35 and is a multifunctional phosphoprotein and plays an active role in ribosomal protein assembly, chromatin remodeling, DNA repair, replication, and transcription.[4] Insertion of 4 bp at exon 12 in NPM1 gene, is one of the most common driver mutations observed in AML cases. The mutant NPM-1 destabilizes tumor suppressor gene protein P14ARF which regulates P53 response.[5] NPM1 mutations are commonly associated with higher complete remission rates and prolonged disease-free and overall survival (OS) with an excellent response to induction chemotherapy.[2]

Co-occurrence of NPM1 and FLT3-TKD is associated with superior relapse-free survival as compared to only NPM1 mutated AML alone. In addition, the prognostic impact of FLT3-TKD on NPM1 mutations is favorable as compared to FLT3-ITD outcomes with a low allelic burden (<0.5).[6] FLT3-TKD mutations represent point mutations in codon D835 or deletions in codon I836 represent a gain of function mutation leading to the activation of tyrosine kinase. A targeted drug and midostaurin, a FLT3 inhibitor has shown to improve event-free survival in patients with FLT3-mutated AML.[7]

WT1 mutations in AML occur in approximately 6%–15% of de novo AML. They occur at a younger age group, show worsened OS, the risk of relapse, and resistance to induction chemotherapy.[8] IDH mutations are CHIP mutations, are stable and persist, and might be present at the time of relapse. The most frequent comutated gene is IDH132H and NPM1. IDH2 mutations show a longer OS as compared to IDH wild type. The IDH1 inhibitor ivosidenib and the IDH2 inhibitor enasidenib are being evaluated in patients in refractory or relapsed AML cases.[9]

AML with mutated NPM1 is a genetically heterogeneous entity of AML and shows multiple associations with other genes. The present case harbored additional mutations such as FLT3 TKD and WT1 which increase the risk of relapse and carry a poor prognosis. It is known that aberrations in IDH2 as CHIP mutations have shown to have better OS than wild-type IDH. However, CHIP mutations like IDH2 act like foundation mutations for other CHOP mutations like NPM1 in AML pathogenesis. It is postulated that NPM1 mutation does not drive CHIP, but often drives leukemia in the presence of underlying CHIP mutations.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: Myeloid and histiocytic/dendritic neoplasms. Leukemia 2022;36:1703. Available from:/pmc/articles/PMC9252913/. [Last accessed on 2022 Sep 25].  Back to cited text no. 1
Fitzpatrick MJ, Hasserjian RP. Separating innocuous “CHIP” mutations from ominous “CHOP” mutations in patients with treated AML in remission. Hematol 2021;18:1. Available from: https://ashpublications.org/thehematologist/article/doi/10.1182/hem.V18.6.202169/477253/Separating-Innocuous-CHIP-Mutations-From-Ominous. [Last accessed on 2022 Sep 26].  Back to cited text no. 2
Cappelli LV, Meggendorfer M, Baer C, Nadarajah N, Hutter S, Jeromin S, et al. Indeterminate and oncogenic potential: CHIP versus CHOP mutations in AML with NPM1 alteration. Leukemia 2022;36:394-402.  Back to cited text no. 3
Heath EM, Chan SM, Minden MD, Murphy T, Shlush LI, Schimmer AD. Biological and clinical consequences of NPM1 mutations in AML. Leukemia 2017;31:798-807.  Back to cited text no. 4
Hindley A, Catherwood MA, McMullin MF, Mills KI. Significance of NPM1 gene mutations in AML. Int J Mol Sci 2021;22:10040.  Back to cited text no. 5
Boddu P, Kantarjian H, Borthakur G, Kadia T, Daver N, Pierce S, et al. Co-occurrence of FLT3-TKD and NPM1 mutations defines a highly favorable prognostic AML group. Blood Adv 2017;1:1546-50.  Back to cited text no. 6
Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: Review of current knowledge and evidence. Leukemia 2019;33:299-312.  Back to cited text no. 7
Rampal R, Figueroa ME. Wilms tumor 1 mutations in the pathogenesis of acute myeloid leukemia. Haematologica 2016;101:672-9.  Back to cited text no. 8
Wouters BJ. Targeting IDH1 and IDH2 mutations in acute myeloid leukemia: Emerging options and pending questions. Hemasphere 2021;5:e583.  Back to cited text no. 9


  [Figure 1], [Figure 2]


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