BRAF inhibitor–associated ERK activation drives development of chronic lymphocytic leukemia

Yaktapour, Niuscha; Meiß, Frank; Mastroianni, Justin; Zenz, Thorsten; Andrlová, Hana; Mathew, Nimitha R.; Claus, Rainer; Hutter, Barbara; Fröhling, Stefan; Brors, Benedikt; Pfeifer, Dietmar; Pantić, Milena; Bartsch, Ingrid; Spehl, Timo S.; Meyer, Philipp T.; Duyster, Justus; Zirlik, Katja; Brummer, Tilman; Zeiser, Robert

doi:10.1172/jci76539

Cited by 55 publications

(54 citation statements)

References 48 publications

(47 reference statements)

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“…30 Furthermore, inhibition of Syk reversed the Erk hyperactivation and led to a decrease in proliferation of CLL cells. 30 Therefore, we speculated that SPRY2, in the presence of RAF inhibition may also inhibit Syk activity in B cells and CLL cells to attenuate MAPK-Erk signaling. To test this hypothesis, we performed immunoprecipitation assays as described in supplemental Methods.…”

Section: Blood 12 May 2016 X Volume 127 Number 19 a Role Of Spry2 Imentioning

confidence: 98%

Sprouty 2: a novel attenuator of B-cell receptor and MAPK-Erk signaling in CLL

Shukla¹,

Rai²,

Shukla³

et al. 2016

Blood

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Key Points• SPRY2 is downregulated in CLL cells from patients with poor prognosis. • SPRY2 is negative regulator of Syk-mediated BCR and MAPK-Erk signaling in CLL.Clinical heterogeneity is a major barrier to effective treatment of chronic lymphocytic leukemia (CLL). Emerging evidence suggests that constitutive activation of various signaling pathways like mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-Erk) signaling plays a role in the heterogeneous clinical outcome of CLL patients. In this study, we have investigated the role of Sprouty (SPRY)2 as a negative regulator of receptor and nonreceptor tyrosine kinase signaling in the pathogenesis of CLL. We show that SPRY2 expression is significantly decreased in CLL cells, particularly from poor-prognosis patients compared with those from good-prognosis patients. Overexpression of SPRY2 in CLL cells from poor-prognosis patients increased their apoptosis. Conversely, downregulation of SPRY2 in CLL cells from good-prognosis patients resulted in increased proliferation. Furthermore, CLL cells with low SPRY2 expression grew more rapidly in a xenograft model of CLL. Strikingly, B-cell-specific transgenic overexpression of spry2 in mice led to a decrease in the frequency of B1 cells, the precursors of CLL cells in rodents. Mechanistically, we show that SPRY2 attenuates the B-cell receptor (BCR) and MAPK-Erk signaling by binding to and antagonizing the activities of RAF1, BRAF, and spleen tyrosine kinase (SYK) in normal B cells and CLL cells. We also show that SPRY2 is targeted by microRNA-21, which in turn leads to increased activity of Syk and Erk in CLL cells. Taken together, these results establish SPRY2 as a critical negative regulator of BCR-mediated MAPK-Erk signaling in CLL, thereby providing one of the molecular mechanisms to explain the clinical heterogeneity of

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Section: Blood 12 May 2016 X Volume 127 Number 19 a Role Of Spry2 Imentioning

confidence: 98%

Sprouty 2: a novel attenuator of B-cell receptor and MAPK-Erk signaling in CLL

Shukla¹,

Rai²,

Shukla³

et al. 2016

Blood

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“…25,38 BRAFi-mediated paradoxical ERK activation was shown to be B-cell-receptor dependent in chronic lymphocytic leukemia cells. 24 We provide further in vivo insight on the risk of BRAFi-driven malignancies and report 1 patient who developed an AML-M6b (subtype pure red cell AML) during vemurafenib treatment. In line with the concept of enhanced paradoxical ERK activation in the context of activated RAS, we identified a PI3K (E545K) mutation in the emerging AML clone, which is known to activate RAS.…”

Section: Discussionmentioning

confidence: 91%

“…Except for 1 patient with keratoacanthoma who received 480 mg of vemurafenib twice daily, all patients with skin tumors received 240 mg twice daily. Progression of non-skin cancer has been reported during vemurafenib treatment, 24,25 which was linked to RASmediated paradox ERK activation of wild-type BRAF in the context of vemurafenib. Patient 12 presented with pure red cell AML-M6b accelerated by vemurafenib treatment (Figure 3).…”

Section: Side Effects During Vemurafenib Treatmentmentioning

confidence: 99%

BRAF inhibition in hairy cell leukemia with low-dose vemurafenib

Dietrich

Pircher

Endris

et al. 2016

Blood

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103

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Key Points• Low doses of the BRAF inhibitor vemurafenib are highly effective in refractory hairy cell leukemia.• Abrogation of BRAF V600E-induced signaling was consistently seen with 240 mg of vemurafenib twice daily.The activating mutation of the BRAF serine/threonine protein kinase (BRAF V600E) is the key driver mutation in hairy cell leukemia (HCL), suggesting opportunities for therapeutic targeting. We analyzed the course of 21 HCL patients treated with vemurafenib outside of trials with individual dosing regimens (240-1920 mg/d; median treatment duration, 90 days). Vemurafenib treatment improved blood counts in all patients, with platelets, neutrophils, and hemoglobin recovering within 28, 43, and 55 days (median), respectively. Complete remission was achieved in 40% (6/15 of evaluable patients) and median event-free survival was 17 months. Response rate and kinetics of response were independent of vemurafenib dosing. Retreatment with vemurafenib led to similar response patterns (n 5 6). Pharmacodynamic analysis of BRAF V600E downstream targets showed that vemurafenib (480 mg/d) completely abrogated extracellular signal-regulated kinase phosphorylation of hairy cells in vivo. Typical side effects also occurred at low dosing regimens. We observed the development of acute myeloid lymphoma (AML) subtype M6 in 1 patient, and the course suggested disease acceleration triggered by vemurafenib. The phosphatidylinositol 3-kinase hotspot mutation (E545K) was identified in the AML clone, providing a potential novel mechanism for paradoxical BRAF activation. These data provide proof of dependence of HCL on active BRAF signaling. We provide evidence that antitumor and side effects are observed with 480 mg vemurafenib, suggesting that dosing regimens in BRAF-driven cancers could warrant reassessment in trials with implications for cost of cancer care. (Blood. 2016;127(23):2847-2855

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“…These AES and SAES require careful monitoring and control of risk factors. An accelerated progression of an RAS‐mutant chronic myelomonocytic leukemia was recently reported after the initiation of vemurafenib therapy in a patient treated for metastatic BRAF‐mutant melanoma,42 as well as in those with CLL in the absence of mutations in RAS43 or AML,41 suggests that the administration of BRAF inhibitors requires careful patient monitoring and evaluation of the treatment in a clinical trial. The combination of a BRAF and MEK inhibitors provides a rational approach for dual vertical inhibition within the MAPK pathway.…”

Section: Treatment Updates (Figures 2 and 3)mentioning

confidence: 96%

Hairy cell leukemia 2018: Update on diagnosis, risk‐stratification, and treatment

Troussard

Cornet

2017

American J Hematol

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Disease overviewHairy cell leukemia (HCL) and HCL‐like disorders, including HCL variant (HCL‐V) and splenic diffuse red pulp lymphoma (SDRPL), are a very heterogeneous group of mature lymphoid B‐cell disorders, characterized by the identification of hairy cells, a specific genetic profile, a different clinical course and the need for appropriate treatment.DiagnosisDiagnosis of HCL is based on morphological evidence of hairy cells, an HCL immunologic score of 3 or 4 based on the CD11C, CD103, CD123, and CD25 expression, the trephine biopsy which makes it possible to specify the degree of tumoral medullary infiltration and the presence of BRAF V600E somatic mutation.Risk stratificationProgression of patients with HCL is based on a large splenomegaly, leukocytosis, a high number of hairy cells in the peripheral blood and the immunoglobulin heavy chain variable region gene mutational status. VH4‐34 positive HCL cases are associated with poor prognosisRisk adapted therapyPurine analogs (PNA) are indicated in symptomatic first line HCL patients. The use of PNA followed by rituximab represents an alternative option.Management of progressive or refractory diseaseIt is based on the use of BRAF inhibitors associated or not with MEK inhibitors, recombinant immunoconjugates targeting CD22 or BCR inhibitors.

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BRAF inhibitor–associated ERK activation drives development of chronic lymphocytic leukemia

Cited by 55 publications

References 48 publications

Sprouty 2: a novel attenuator of B-cell receptor and MAPK-Erk signaling in CLL

Sprouty 2: a novel attenuator of B-cell receptor and MAPK-Erk signaling in CLL

BRAF inhibition in hairy cell leukemia with low-dose vemurafenib

Hairy cell leukemia 2018: Update on diagnosis, risk‐stratification, and treatment

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