Clonal chromosome rearrangements in hairy cell leukemia: personal experience and review of literature

doi:10.1016/S0165-4608(01)00448-4

Cancer Genetics and Cytogenetics

Volume 129, Issue 2, September 2001, Pages 138-144

https://doi.org/10.1016/S0165-4608(01)00448-4 Get rights and content

Abstract

Cytogenetic studies in hairy cell leukemia (HCL) are rare. In the present report, cytogenetic investigations were performed on marrow cells obtained from 21 HCL male patients with a mean age of 57 years and active disease. Karyotypic analysis was successful in 18 of the 21 patients, either at diagnosis or in relapse after treatment with IFNa. Clonal chromosome abnormalities were detected in eight of 18 cases. The chromosome most frequently involved in the rearranged karyotypes was chromosome 14. Results are discussed with respect to 79 abnormal HCL cases obtained from an extensive review of the literature from 1978 to 2000.

Introduction

Hairy cell leukemia (HCL) is a rare B-lymphoproliferative disorder, which comprises about 2% of all leukemias and affects men four times as frequently as women, with a median age of 50 years. The disease is characterized by the presence of circulating hairy cells, which are large differentiated B cells with cytoplasmic projections. Pancytopenia and splenomegaly are very common findings in HCL patients. HCL is a chronic, frequently progressive disease and mortality is often due to infection 1, 2. Since treatment with recombinant interferon-a (IFNa) has been widely used, the prognosis is relatively good. IFNa is associated with a high response rate, with approximately 80% of the patients showing hematological improvement [3].

Only a few cytogenetic studies on HCL have been reported. This is mostly due to the rarity of the disease and the difficulties in obtaining adequate material from bone marrow aspirate. Moreover, hairy cells present low responsiveness to common mitogens. Since 1978, when the first clonal aberrations were reported in HCL [4], 79 cases with abnormal karyotypes have been described 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28. The most frequent cytogenetic abnormalities reported in the literature involve chromosomes 3, 5, 6, 7, 10, 12, 14, 17, and Y [29].

Herein, the cytogenetic findings in a series of 21 patients are presented. The results are pooled and discussed in comparison with the chromosome abnormalities published so far in HCL.

Section snippets

Patients and methods

Cytogenetic studies were performed on marrow cells obtained from 21 males with a median age of 57 years (range: 46–84 years). The diagnosis was based on typical findings in bone marrow biopsies and aspirates by means of cytochemistry (TRAP positivity) and flow cytometry (expression of CD19, CD20, CD25 B-cell markers). All patients had active disease. Ten of them were sampled at diagnosis, whereas the remaining 11 were in relapse, having received IFNa as the only treatment. The karyotypic

Results

Eighteen out of twenty-one patients were evaluable; no mitoses were found in three cases. In eight cases, clonal abnormalities were identified (44.4%). Six of the eight patients with clonal aberrations were analyzed at diagnosis. Chromosome 14 was most frequently involved in the rearranged karyotypes (Table 1). Structural abnormalities of chromosome 14 were observed as the only chromosomal change in three out of eight cases at diagnosis. Among them, case 11 showed a 14q+ marker, while cases 14

Discussion

In the present study, clonal chromosome alterations were detected in eight of the 18 cytogenetically evaluable HCL cases (44.4%). Clonal aberrations were revealed in six out of eight untreated patients (75%) and in a quite lower frequency in the patients being in relapse after treatment with IFNa (2/10, 20%). In previously published series of patients with HCL, the incidence of clonal aberrations is variable 10, 11, 18, 20. This is probably due to the different clinical status, the variety of

Acknowledgements

Cristina Mecucci was partially supported by AIRC, Associazione Italiana per la Ricerca sul Cancro.

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Hairy cell leukemia (HCL) is a distinct clinicopathological entity whose underlying genetic lesion has remained a mystery for over half a century. The BRAF V600E mutation is now recognized as the causal genetic event of HCL because it is somatic, present in the entire tumor clone, detectable in almost all cases at diagnosis (encompassing the whole disease spectrum), and stable at relapse. BRAF V600E leads to the constitutive activation of the RAF-MEK-extracellular signal-regulated kinase (ERK) signaling pathway which represents the key event in the molecular pathogenesis of HCL. KLF2 and CDNK1B (p27) mutations may cooperate with BRAF V600E in promoting leukemic transformation. Sensitive molecular assays for detecting BRAF V600E allow HCL (highly responsive to purine analogs) to be better distinguished from HCL-like disorders, which are treated differently. In vitro preclinical studies on purified HCL cells proved that BRAF and MEK inhibitors can induce marked dephosphorylation of MEK/ERK, silencing of RAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression profile signature, change of morphology from “hairy” to “smooth,” and eventually apoptosis. The overall response rate of refractory/relapsed HCL patients to the BRAF inhibitor vemurafenib approached 100%, with 35% to 40% complete remissions (CRs). The median relapse free-survival was about 19 months in patients who had achieved CR and 6 months in those who had obtained a partial response. Future therapeutic perspectives include: (1) combining BRAF inhibitors with MEK inhibitors or immunotherapy (anti-CD20 monoclonal antibody) to increase the percentage of CRs and (2) better understanding of the molecular mechanisms underlying resistance of HCL cells to BRAF inhibitors.
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Original articleClonal chromosome rearrangements in hairy cell leukemia: personal experience and review of literature

Abstract

Introduction

Section snippets

Patients and methods

Results

Discussion

Acknowledgements

Leuk Res

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Leuk Res

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Blood

Blood

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Leuk Res

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Blood

Original article
Clonal chromosome rearrangements in hairy cell leukemia: personal experience and review of literature