A microRNA signature specific for hairy cell leukemia and associated with modulation of the MAPK–JNK pathways

Kitagawa, Yukiko; Brahmachary, Manisha; Tiacci, Enrico; Dalla‐Favera, Riccardo; Falini, Brunangelo; Basso, Katia

doi:10.1038/leu.2012.149

Cited by 14 publications

(17 citation statements)

References 15 publications

(35 reference statements)

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“…[1][2][3][4][5] The latter include not only exquisite initial sensitivity to myelotoxic chemotherapy with purine analogs, but also frequent relapses accompanied by a progressive loss of response to these drugs with time, 6,7 calling for new therapeutic strategies. We recently discovered that HCL is a unique hematologic neoplasm also genetically, in that the BRAF-V600E kinase-activating mutation is present in virtually all HCL patients whereas it is exceptionally rare in all other blood tumors, 28 including HCL mimics such as splenic marginal zone lymphoma with villous lymphocytes and HCL variant.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4][5] Patients with HCL typically present with pancytopenia, splenomegaly in the absence of significant lymphadenopathy, and infiltration of the bone marrow, spleen, and liver by leukemic cells with peculiar hairy projections emanating from their cell membrane. These leukemic hairy cells circulate usually in low numbers in the peripheral blood and are difficult to aspirate from the bone marrow due to HCL-induced marrow fibrosis.…”

Section: Introductionmentioning

confidence: 99%

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BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity

Pettirossi

Santi

Imperi

et al. 2015

Blood

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Key Points• The V600E kinase-activating mutation of BRAF profoundly shapes the distinct identity of HCL among B-cell neoplasms.• Clinically available BRAF and MEK inhibitors exert potent antileukemic activity in patients' HCL cells in vitro and in vivo.Hairy cell leukemia (HCL) shows unique clinicopathological and biological features. HCL responds well to purine analogs but relapses are frequent and novel therapies are required. BRAF-V600E is the key driver mutation in HCL and distinguishes it from other B-cell lymphomas, including HCL-like leukemias/lymphomas (HCL-variant and splenic marginal zone lymphoma). The kinase-activating BRAF-V600E mutation also represents an ideal therapeutic target in HCL. Here, we investigated the biological and therapeutic importance of the activated BRAF-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway in HCL by exposing in vitro primary leukemic cells purified from 26 patients to clinically available BRAF (vemurafenib; dabrafenib) or MEK (trametinib) inhibitors. Results were validated in vivo in samples from vemurafenib-treated HCL patients within a phase 2 clinical trial. BRAF and MEK inhibitors caused, specifically in HCL (but not HCL-like) cells, marked MEK/ERK dephosphorylation, silencing of the BRAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression signature, downregulation of the HCL markers CD25, tartrate-resistant acid phosphatase, and cyclin D1, smoothening of leukemic cells' hairy surface, and, eventually, apoptosis. Apoptosis was partially blunted by coculture with bone marrow stromal cells antagonizing MEK-ERK dephosphorylation. This protective effect could be counteracted by combined BRAF and MEK inhibition. Our results strongly support and inform the clinical use of BRAF and

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity

Pettirossi

Santi

Imperi

et al. 2015

Blood

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“…Hairy cell leukemia is a chronic mature B-cell malignancy with unique clinicopathologic and biologic features 1-4 . Purine analogues (cladribrine; pentostatin) induce durable complete remissions in ~80% of HCL cases 5,6 .…”

Section: Introductionmentioning

confidence: 99%

Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia

Park²,

et al. 2015

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BACKGROUND BRAF-V600E is the genetic lesion underlying hairy cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy cell leukemia who relapsed after or were refractory to purine analogues. METHODS We conducted in Italy and USA two phase-2 single-arm multicenter studies of vemurafenib (960 mg twice daily) given for a median of 16 and 18 weeks, respectively. Primary endpoints were complete remission rate and overall response rate. Patient enrollment was completed (n=28) in the Italian trial in April 2013 and is still open (n=26/36) in the American trial. RESULTS Drug-related adverse events were usually of grade 1-2, and those most frequently requiring dose reductions were rash and arthralgia/arthritis; secondary cutaneous tumors (treated with simple excision) developed in 6/50 patients. Overall response rates were 96% (25/26 evaluable Italian patients) and 100% (24/24 evaluable American patients), obtained after a median of 8 weeks and 12 weeks, respectively. Complete response rates were 34.6% (9/26) and 41.7% (10/24), respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free and treatment-free survivals were respectively 19 and 25 months in complete responders, and 6 and 18 months in partial responders. In the American trial, 1-year progression-free and overall survival were 73% and 91%, respectively. Frequent persistence of phospho-ERK+ bone marrow leukemic cells at the end of treatment suggests bypass MEK-ERK reactivation as a resistance mechanism. CONCLUSIONS A short oral course of vemurafenib proved safe and highly effective in relapsed/refractory hairy cell leukemia patients (Funded by AIRC, ERC, Roche/Genentech and others; EudractCT number: 2011-005487-13, ClinicalTrials.gov number NCT01711632).

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“…Nevertheless, genome-wide studies analyzing the expression of protein-coding and microRNA genes 10,11 were successfully performed and unraveled a transcriptional signature specific of HCL that provided important insights into its putative cell of origin (ie, a germinal center–experienced memory B cell) and into some of its biologic properties (eg, the typical morphology, the bone marrow fibrosis, and the selective dissemination pattern to certain anatomic sites). 12 …”

Section: Earlier Genomic Studiesmentioning

confidence: 99%

Genomics of Hairy Cell Leukemia

Tiacci

Pettirossi

Schiavoni

et al. 2017

JCO

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Hairy cell leukemia (HCL) is a chronic mature B-cell neoplasm with unique clinicopathologic features and an initial exquisite sensitivity to chemotherapy with purine analogs; however, the disease relapses, often repeatedly. The enigmatic pathogenesis of HCL was recently clarified by the discovery of its underlying genetic cause, the BRAF-V600E kinase-activating mutation, which is somatically and clonally present in almost all patients through the entire disease spectrum and clinical course. By aberrantly activating the RAF-MEK-ERK signaling pathway, BRAF-V600E shapes key biologic features of HCL, including its specific expression signature, hairy morphology, and antiapoptotic behavior. Accompanying mutations of the KLF2 transcription factor or the CDKN1B/p27 cell cycle inhibitor are recurrent in 16% of patients with HCL and likely cooperate with BRAF-V600E in HCL pathogenesis. Conversely, BRAF-V600E is absent in other B-cell neoplasms, including mimickers of HCL that require different treatments (eg, HCL-variant and splenic marginal zone lymphoma). Thus, testing for BRAF-V600E allows for a genetics-based differential diagnosis between HCL and HCL-like tumors, even noninvasively in routine blood samples. BRAF-V600E also represents a new therapeutic target. Patients’ leukemic cells exposed ex vivo to BRAF inhibitors are spoiled of their HCL identity and then undergo apoptosis. In clinical trials of patients with HCL who have experienced multiple relapses after purine analogs or who are refractory to purine analogs, a short course of the oral BRAF inhibitor vemurafenib produced an almost 100% response rate, including complete remission rates of 35% to 42%, without myelotoxicity. To further improve on these results, it will be important to clarify the mechanisms of incomplete leukemic cell eradication by vemurafenib and to explore chemotherapy-free combinations of a BRAF inhibitor with other targeted agents (eg, a MEK inhibitor and/or an anti-CD20 monoclonal antibody).

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A microRNA signature specific for hairy cell leukemia and associated with modulation of the MAPK–JNK pathways

Cited by 14 publications

References 15 publications

BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity

BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity

Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia

Genomics of Hairy Cell Leukemia

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