The following case study focuses on a previously healthy 32-year-old
male, who went to his primary care physician’s clinic for generalized
ecchymoses and palpitations lasting two days. There were no other
accompanying symptoms. Test your knowledge by reading the background
information below and making the proper selection.
Vital signs and physical examination were significant only for
tachycardia (HR=110) and multiple generalized ecchymoses. The rest of
the physical exam findings and review of systems were unremarkable. The
patient denied taking any medications. A complete blood count (CBC)
showed the following: white blood count 2.4 x 103/μl, hemoglobin 9.5
g/dl, hematocrit 28, mean corpuscular volume 98.6 fl, platelet count 13
x 109/μL, absolute neutrophil count 1.2 x 103/μl, peripheral blasts 20
percent. A diagnosis of acute leukemia was suspected. The patient was
referred to a hematologist who performed a bone marrow biopsy and
confirmed the diagnosis of acute myeloid leukemia (AML). The patient
had a normal male karyotype by metaphase cytogenetics. The hematologist
ordered additional molecular tests to guide in the prognostic
stratification of this patient.
Which findings will impart the best prognostic outcome after induction chemotherapy in this patient?
- Cytoplasmic nucleophosmin-1 (NPM-1) positive, FMS-like tyrosine kinase-3 (Flt-3) internal tandem duplication (ITD) negative
- Cytoplasmic NPM-1 negative, Flt-3 ITD positive
- Cytoplasmic NPM-1 positive, Flt-3 ITD positive
- Cytoplasmic NPM-1 negative, Flt-3 ITD negative
- Cytoplasmic NPM-1 positive, Flt-3 ITD negative
Nucleophosmin-1 (NPM-1) is a nucleocytoplasmic protein encoded by the NPM-1
gene located on chromosome 5q35.1. It serves many functions including
centrosome assembly, regulation of protein shuttling through the
nuclear membrane, control of ribosome biosynthesis, and regulation of
the AFR/p53 suppressor pathway. It is normally localized in the
nucleolus, but mutation of the NPM-1 gene results in
cytoplasmic localization of the NPM-1 protein (NPM-1c) due to a
combination of the loss of two key tryptophans, 288 and 290, which
alters the localization of NPM away from the nucleoli as well as the
generation of a new Rev-type nuclear export sequence at the C terminus.
Patients with primary AML who have cytoplasmic localization of NPM-1
typically have normal cytogenetics. The presence of NPM-1c can be a
good prognostic marker with regard to event-free survival (EFS) and
overall survival (OS) after chemotherapy. FMS-like tyrosine kinase-3
(Flt-3) is a receptor found in normal hematopoietic stem/progenitor
cells and is important in normal hematopoietic stem/progenitor cell
survival, proliferation, and differentiation. Abnormalities of the
Flt-3 receptor may include either an internal tandem duplication (ITD)
of the juxtamembrane domain or a mutation of the tyrosine kinase domain
(D835 or I836). The presence of the Flt-3 ITD mutation has been
implicated in worse EFS and OS. Döhner and colleagues analyzed the
results of induction chemotherapy in patients ≤60 years old with a
normal karyotype enrolled in the AML HD93 and AML HD98-A trials. The
results indicated that NPM-1 mutations predicted for better responseto induction chemotherapy and improved OS only in the absenceof the Flt-3 ITD mutation.
- Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352:254-66.
- Kottaridis PD, Gale RE, Frew ME, et al. The
presence of a Flt-3 internal tandem duplication in patients with acute
myeloid leukemia (AML) adds important prognostic information to
cytogenetic risk group and response to the first cycle of chemotherapy:
analysis of 854 patients from the United Kingdom Medical Research
Council AML 10 and 12 trials. Blood. 2001;98:1752-9.
- Döhner K, Schlenk RF, Habdank M, et al. Mutant nucleophosmin (NPM1)
predicts favorable prognosis in younger adults with acute myeloid
leukemia and normal cytogenetics: interaction with other gene mutations. Blood. 2005;106:3740-6.
- Falini B, Nicoletti I, Martelli MF, et al. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. Blood. 2007;109:874–85.
- Albiero E, Madeo D, Bolli N, et al. Identification
and functional characterization of a cytoplasmic nucleophosmin
leukaemic mutant generated by a novel exon-11 NPM1 mutation. Leukemia. 2007; 21:1099–103.
- Falini B, Bolli N, Shan J, et al. Both
carboxy-terminus NES motif and mutated tryptophan(s) are crucial for
aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML. Blood. 2006;107:4514–23.
- Falini B. Acute Myeloid Leukemia with Mutated Nucleophosmin. Clinical Leukemia. 2008;2:163-173.
Case study submitted by Ramon V. Tiu, MD, BS, of the Cleveland Clinic.
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