Letter to the Editor

Chronic myeloid leukemia, BCR-ABL1-positive, carrying NPM1 mutation – First case series from a single institution

Nucleophosmin 1 (NPM1) is located on chromosome 5q35 and encodes nucleophosmin, a predominantly nucleolar protein that shuttles between the nucleus and cytoplasm of cells. Nucleophosmin plays several important roles at the cellular level including acting as a chaperone, preventing the aggregation of proteins in the nucleolus, and assembling proteins in the ribosome. Perhaps more importantly, nucleophosmin plays a vital role in regulating tumor suppressor pathways, particularly the ARF-p53 pathway [[1], [2], [3]]. Mutations in NPM1 typically occur in exon 11 (formerly identified as exon 12) and are characterized by aberrant cytoplasmic expression of NPM1, as can be shown by immunohistochemical analysis [2]. NPM1 mutation is considered somewhat specific for acute myeloid leukemia (AML), although mutation may be rarely observed in other hematological neoplasms such as myelodysplastic syndrome and chronic myelomonocytic leukemia (CMML) [[4], [5], [6]]. About two thirds of AML cases with a normal karyotype in adults bear NPM1 mutations [7]. The presence of NPM1 mutation in patients with AML portends a favorable prognosis, particularly in the absence of FLT3-ITD or FLT3-ITD mutation with a low allelic ratio (<0.5) or other mutations per 2017 European Leukemia Net (ELN) guidelines [3,[7], [8], [9]]. Patients with isolated NPM1 mutation respond well to induction chemotherapy and typically do not require stem cell transplantation [9]. NPM1 mutation status therefore plays a role in evaluating a patient’s risk of relapse and in monitoring minimal residual disease [9].

BCR-ABL1 is the product of a reciprocal translocation involving BCR on chromosome 22q11.2 and ABL on chromosome 9q34.1, leading to the formation of a fusion gene on the derivative chromosome 22, also known as the Philadelphia chromosome (Ph). BCR-ABL1 is a definitional feature of chronic myeloid leukemia (CML), but also occurs in 20–30% of cases of B-lymphoblastic leukemia and <1% of cases of acute myeloid leukemia [7]. BCR-ABL fusion protein is a tyrosine kinase that activates several pathways leading to leukemogenesis [10], and can be inhibited by tyrosine kinase inhibitors such as imatinib and ponatinib [10].

Several groups have analyzed a total of 356 CML patients and failed to identify a single CML patient carrying NPM1 mutation [[11], [12], [13], [14], [15]]. Therefore NPM1 mutation has been thought be mutually exclusive with BCR-ABL1 in this context [16]. Contrary to this hypothesis, we have identified a series of three patients with simultaneous BCR-ABL1 and NPM1 mutation at a single institution. Based on the total number of CML patients who underwent testing for both abnormalities over a period of 8 years, the incidence of NPM mutation is approximately 0.3%. By comprehensive evaluation, we have demonstrated that these patients represent CML in myeloid blast phase with NPM1 mutation rather than AML with BCR-ABL1.