Two myeloid leukemia cases with rare <i>FLT3</i> fusions

Zhang, Haijiao; Paliga, Aleksandra; Hobbs, Evie; Moore, Stephen; Olson, Susan B.; Long, Nicola; Dao, Kim; Tyner, Jeffrey W.

doi:10.1101/mcs.a003079

Cited by 20 publications

(19 citation statements)

References 20 publications

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“…Fusions involving the tyrosine kinase genes PDGFRB ( SPECC1 - PDGFRB and NDEL1-PDGFRB ) and FLT3 ( CCDC88C - FLT3 ) were also identified in case reports of JMML-diagnosed patients lacking mutations in the classical JMML drivers [ 65 , 66 , 67 ]. Similar rearrangements involving these tyrosine kinases have been also described in other hematologic malignancies [ 68 , 69 , 70 , 71 , 72 ], supporting the role for these alterations as an alternative oncogenic mechanism of RAS pathway hyperactivation in leukemia transformation. However, although these patients harboring tyrosine kinase fusions recapitulate the clinical features of JMML, it is still a matter of controversy whether they should be diagnosed as JMML or instead represent an as yet undefined category of myelodysplastic/myeloproliferative neoplasms.…”

Section: Genetic Alterations In Jmmlsupporting

confidence: 71%

Genomic and Epigenomic Landscape of Juvenile Myelomonocytic Leukemia

Fiñana

Gómez-Molina

Alonso-Moreno

et al. 2022

Cancers

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Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative neoplasm of early childhood. Most of JMML patients experience an aggressive clinical course of the disease and require hematopoietic stem cell transplantation, which is currently the only curative treatment. JMML is characterized by RAS signaling hyperactivation, which is mainly driven by mutations in one of five genes of the RAS pathway, including PTPN11, KRAS, NRAS, NF1, and CBL. These driving mutations define different disease subtypes with specific clinico-biological features. Secondary mutations affecting other genes inside and outside the RAS pathway contribute to JMML pathogenesis and are associated with a poorer prognosis. In addition to these genetic alterations, JMML commonly presents aberrant epigenetic profiles that strongly correlate with the clinical outcome of the patients. This observation led to the recent publication of an international JMML stratification consensus, which defines three JMML clinical groups based on DNA methylation status. Although the characterization of the genomic and epigenomic landscapes in JMML has significantly contributed to better understand the molecular mechanisms driving the disease, our knowledge on JMML origin, cell identity, and intratumor and interpatient heterogeneity is still scarce. The application of new single-cell sequencing technologies will be critical to address these questions in the future.

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Section: Genetic Alterations In Jmmlsupporting

confidence: 71%

Genomic and Epigenomic Landscape of Juvenile Myelomonocytic Leukemia

Fiñana

Gómez-Molina

Alonso-Moreno

et al. 2022

Cancers

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“…It will be interesting to see how these patients respond to newer‐generation FLT3 inhibitors such as midostaurin and gilteritinib, which are more specific and more powerful compared to earlier inhibitors. Hydroxycarbamide, a ribonucleotide reductase inhibitor, induced complete haematological and cytogenetic responses in two patients with FLT3 rearrangement, although both cases relapsed after one year 11,12 . Our patient also responds well to hydroxycarbamide and is under close monitoring of the peripheral blood count.…”

Section: Figurementioning

confidence: 54%

“…Hydroxycarbamide, a ribonucleotide reductase inhibitor, induced complete haematological and cytogenetic responses in two patients with FLT3 rearrangement, although both cases relapsed after one year. 11,12 Our patient also responds well to hydroxycarbamide and is under close monitoring of the peripheral blood count. Currently, bone marrow transplantation remains the standard of care for longterm survival in this group of deadly diseases.…”

Section: Zbtb44-flt3 Fusion In a Patient With A Myeloproliferative Nementioning

confidence: 71%

ZBTB44–FLT3 fusion in a patient with a myeloproliferative neoplasm

et al. 2020

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haemophagocytosis, however, is often a sign of systemic inflammation and may predict mortality. Severe infections with or without haemophagocytic lymphohistiocytosi are important differential diagnoses. From personal experience, peripheral haemophagocytosis can be readily spotted so long as the observer is prepared to find it. In all cases, haemophagocytosis was found during the first five minutes of examination with magnification at 9400 (objective 940). Kuwata et al. 1 described a blunt-edged preparation of blood smears in which the spreader slide was stopped abruptly towards the end of the spread. It was said that leukocytes near the blunt end were evenly distributed and had clear morphology for the identification of haemophagocytosis. In conclusion, peripheral haemophagocytosis is a sign worth looking out for among hospitalised children. Singlelineage erythrophagocytosis is a sign of acquired haemolysis while multilineage haemophagocytosis is often indicative of systemic inflammation and life-threatening illnesses.

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“…Another fusion between thyroid hormone receptor interactor 11 (TRIP11) and FLT3 [TRIP11-FLT3, due to (13,14)(q12;q32) rearrangement] was described in myeloproliferative disease (47), but the function of this fusion protein remains to be determined. In addition to myeloproliferative disease, ETV-FLT3 fusion was reported in chronic myelomonocytic leukemia (360). Other FLT3 fusion includes GOLGB1-FLT3 [due to t(3,13)(q13;q12) rearrangement] was described in atypical mixed lymphoid/ myeloid neoplasm (312), SPTBN1-FLT3 fusion in atypical chronic myeloid leukemia (89), ZMYM2-FLT3 fusion in myeloid neoplasms with eosinophilia (117), and MYO18A-FLT3 fusion in atypical chronic myeloid leukemia (360).…”

Section: B Flt3 Mutations In Human Diseasementioning

confidence: 99%

“…In addition to myeloproliferative disease, ETV-FLT3 fusion was reported in chronic myelomonocytic leukemia (360). Other FLT3 fusion includes GOLGB1-FLT3 [due to t(3,13)(q13;q12) rearrangement] was described in atypical mixed lymphoid/ myeloid neoplasm (312), SPTBN1-FLT3 fusion in atypical chronic myeloid leukemia (89), ZMYM2-FLT3 fusion in myeloid neoplasms with eosinophilia (117), and MYO18A-FLT3 fusion in atypical chronic myeloid leukemia (360).…”

Section: B Flt3 Mutations In Human Diseasementioning

confidence: 99%

FMS-like Tyrosine Kinase 3/FLT3: From Basic Science to Clinical Implications

Kazi

Rönnstrand

2019

Physiological Reviews

140

147

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FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is expressed almost exclusively in the hematopoietic compartment. Its ligand, FLT3 ligand (FL), induces dimerization and activation of its intrinsic tyrosine kinase activity. Activation of FLT3 leads to its autophosphorylation and initiation of several signal transduction cascades. Signaling is initiated by the recruitment of signal transduction molecules to activated FLT3 through binding to specific phosphorylated tyrosine residues in the intracellular region of FLT3. Activation of FLT3 mediates cell survival, cell proliferation, and differentiation of hematopoietic progenitor cells. It acts in synergy with several other cytokines to promote its biological effects. Deregulated FLT3 activity has been implicated in several diseases, most prominently in acute myeloid leukemia where around one-third of patients carry an activating mutant of FLT3 which drives the disease and is correlated with poor prognosis. Overactivity of FLT3 has also been implicated in autoimmune diseases, such as rheumatoid arthritis. The observation that gain-of-function mutations of FLT3 can promote leukemogenesis has stimulated the development of inhibitors that target this receptor. Many of these are in clinical trials, and some have been approved for clinical use. However, problems with acquired resistance to these inhibitors are common and, furthermore, only a fraction of patients respond to these selective treatments. This review provides a summary of our current knowledge regarding structural and functional aspects of FLT3 signaling, both under normal and pathological conditions, and discusses challenges for the future regarding the use of targeted inhibition of these pathways for the treatment of patients.

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Two myeloid leukemia cases with rare FLT3 fusions

Cited by 20 publications

References 20 publications

Genomic and Epigenomic Landscape of Juvenile Myelomonocytic Leukemia

Genomic and Epigenomic Landscape of Juvenile Myelomonocytic Leukemia

ZBTB44–FLT3 fusion in a patient with a myeloproliferative neoplasm

FMS-like Tyrosine Kinase 3/FLT3: From Basic Science to Clinical Implications

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