Advances in understanding the pulmonary infiltration in acute promyelocytic leukaemia

Luesink, Maaike; Jansen, Joop H.

doi:10.1111/j.1365-2141.2010.08325.x

Cited by 46 publications

(36 citation statements)

References 98 publications

(204 reference statements)

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“…It has been suggested that ligand-activated PML-RARA directly induces chemokine expression in differentiating APL cells, thereby triggering DS development. 9,10 Because FNDC3B-RARA is a potent transcriptional activator at pharmacological ATRA doses, it may be possible that the hyperactivated RARA signaling during ATRA therapy causes chemokine overproduction and early DS in our patient, who lacks risk factors for DS including high white blood cell counts, abnormal serum creatinine levels, and FLT3-internal tandem duplication.…”

mentioning

confidence: 99%

FNDC3B is another novel partner fused to RARA in the t(3;17)(q26;q21) variant of acute promyelocytic leukemia

Cheng

Wang

Wong

et al. 2017

Blood

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Acute promyelocytic leukemia (APL) is characterized by the promyelocytic leukemia-retinoic acid receptor a (PML-RARA) fusion. In rare instances, RARA is fused to other partners, which dictate sensitivity to targeted therapies. Chen et al previously reported in Blood a novel TBLR1-RARA fusion, which is all-trans-retinoic acid (ATRA)-insensitive in vivo, in a t(3;17)(q26;q21)-harboring APL. 1,2 Here, we report another new RARA fusion resulting from the same translocation in a variant APL patient.The patient was a 36-year-old man who presented with fatigue, dyspnea, and easy bruising for 2 weeks. Complete blood count revealed a hemoglobin level of 5.4 g/dL, platelet count of 41 3 10 9 /L, and white blood cell count of 3.6 3 10 9 /L with 60% hypergranular blasts. Clotting profile showed a decreased fibrinogen level and prolonged prothrombin time but normal activated partial thromboplastin time. Bone marrow (BM) examination showed 68% of blasts with morphology similar to those in peripheral smear ( Figure 1A). The blasts were positive for myeloperoxidase, CD13, CD15, CD33, and CD117 but negative for CD34 and HLA-DR by flow cytometry. A diagnosis of APL was suggested and ATRA (45 mg/m 2 per day) was initiated while awaiting molecular findings. On day 4 of ATRA therapy, the patient developed differentiation syndrome (DS) with fluid retention and pleural effusions. Steroids and diuretics were started, and the 7 1 3 induction chemotherapy was commenced with cytarabine (200 mg/m 2 ) and daunorubicin (60 mg/m 2 ). A morphological complete remission was confirmed at day 30. Figure 1B-C) but the expected TBLR1-RARA fusion previously identified in t(3;17) was absent. No mutations in FLT3, NPM1, CEBPA, DNMT3A, RUNX1, K/NRAS, WT1, or IDH1/2 were detected. Using 59-rapid amplification of complementary DNA ends, we found that RARA was fused to another 3q26 gene called fibronectin type III (FN3) domain containing 3B (FNDC3B) in our patient. Subsequent RT-PCR confirmed the fusion between exon 24 of FNDC3B and exon 3 of RARA ( Figure 1D), which is involved in all other RARA fusions. FNDC3B was originally identified as an adipocyte differentiation factor.3 It contains 9 FN3 domains, which are implicated in protein interactions. The full-length FNDC3B-RARA transcript is predicted to encode a 1461-amino acid protein, containing 8 FN3 domains of FNDC3B as well as the DNA-binding and ligand-binding domain of RARA ( Figure 1E). Two reciprocal RARA-FNDC3B transcripts were also detected. The major transcript involves an in-frame fusion between RARA exon 2 and FNDC3B exon 25, whereas the minor transcript involves an out-offrame fusion between the same RARA exon and FNDC3B exon 26 ( Figure 1D). These transcripts are expected to generate 205-and 111-amino acid proteins, respectively ( Figure 1E). Both FNDC3B-RARA and RARA-FNDC3B fusions were undetected after the patient

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mentioning

confidence: 99%

FNDC3B is another novel partner fused to RARA in the t(3;17)(q26;q21) variant of acute promyelocytic leukemia

Cheng

Wang

Wong

et al. 2017

Blood

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“…In this context, IL-8, MCP-1, IL-1β and GRO-α play an important role in inducing transmigration of differentiated APL cells from blood stream into alveolar space [1,2,3,29,30]. In contrast to these studies, we studied the mechanism underlying the clearance of apoptotic APL cells during resolution phase in DS patients.…”

Section: Discussionmentioning

confidence: 90%

CX3CL1(+) Microparticles Mediate the Chemoattraction of Alveolar Macrophages toward Apoptotic Acute Promyelocytic Leukemic Cells

Tsai

Shih

Feng³

et al. 2014

Cell Physiol Biochem

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Background/Aims: During the resolution phase of inflammation, release of “find-me” signals by apoptotic cells is crucial in the chemoattraction of macrophages toward apoptotic cells for subsequent phagocytosis, in which microparticles derived from apoptotic cells (apo-MPs) are involved. A recent study reports that CX3CL1 is released from apoptotic cells to stimulate macrophages chemotaxis. In this study, we investigated the role of CX3CL1 in the apo-MPs in the cell-cell interaction between alveolar macrophage NR8383 cells and apoptotic all-trans retinoic acid-treated NB4 (ATRA-NB4) cells. Methods/Results: Apoptotic ATRA-NB4 cells and their conditioning medium (CM) enhanced the chemoattraction of NR8383 cells as well as their phagocytosis activity in engulfing apoptotic ATRA-NB4 cells. The levels of CX3CL1(+) apo-MPs and CX3CL1 were rapidly elevated in the CM of ATRA-NB4 cell culture after induction of apoptosis. Both exogenous CX3CL1 and apo-MPs enhanced the transmigration of NR8383 cells toward apoptotic ATRA-NB4 cells. This pro-transmigratory activity was able to be partially inhibited either by blocking the CX3CR1 (CX3CL1 receptor) of NR8383 cells with its specific antibody or by blocking the surface CX3CL1 of apo-MPs with its specific antibody before incubating these apo-MPs with NR8383 cells. Conclusion: CX3CL1(+) apo-MPs released by apoptotic cells mediate the chemotactic transmigration of alveolar macrophages.

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“…The condition can manifest as fever, oedema, hypotension, dyspnea, weight gain >5 kg and musculoskeletal pain 18,19 . The signs and symptoms together with pulmonary infiltrates often lead to the misdiagnosis of DS as pneumonia.…”

Section: Apml Differentiation Syndromementioning

confidence: 99%

Haematological Emergencies

Tay

2014

Proceedings of Singapore Healthcare

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In a hospital setting, it is common to encounter certain haematological emergencies irrespective of whether or not the patient has an underlying haematological condition or if the hospital has a well-established haematology service. This article aims to define and illustrate common and less common haematological emergencies that a physician may encounter on the wards and the appropriate initial management for the patient prior to a formal hematological consult.

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Advances in understanding the pulmonary infiltration in acute promyelocytic leukaemia

Cited by 46 publications

References 98 publications

FNDC3B is another novel partner fused to RARA in the t(3;17)(q26;q21) variant of acute promyelocytic leukemia

FNDC3B is another novel partner fused to RARA in the t(3;17)(q26;q21) variant of acute promyelocytic leukemia

CX3CL1(+) Microparticles Mediate the Chemoattraction of Alveolar Macrophages toward Apoptotic Acute Promyelocytic Leukemic Cells

Haematological Emergencies

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