Concurrent juvenile myelomonocytic leukemia and T‐lymphoblastic lymphoma with a shared missense mutation in <i>NRAS</i>

Ly, Brenda; Modi, Arunkumar; Rogers, Heesun J.; Makishima, Hideki; Hanna, Rabi; Cook, James R.; Theil, Karl S.; Maciejewski, Jaroslaw P.

doi:10.1002/pbc.24797

Cited by 7 publications

(6 citation statements)

References 17 publications

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“…Our T-cell findings have notable parallels in JMML patients. Occasionally, these children acquire T-ALL either concurrently with their MPN or after the resolution of their myeloid disease [ 18 , 34 – 36 ]. Our observation of decreased naïve peripheral T cells and increased thymic precursors may provide a mechanistic explanation for this association.…”

Section: Discussionmentioning

confidence: 99%

Hematopoietic-restricted Ptpn11E76K reveals indolent MPN progression in mice

Tarnawsky

Wang

et al. 2018

Oncotarget

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Juvenile Myelomonocytic Leukemia (JMML) is a pediatric myeloproliferative neoplasm (MPN) that has a poor prognosis. Somatic mutations in Ptpn11 are the most frequent cause of JMML and they commonly occur in utero. Animal models of mutant Ptpn11 have probed the signaling pathways that contribute to JMML. However, existing models may inappropriately exacerbate MPN features by relying on non-hematopoietic-restricted Cre-loxP strains or transplantations into irradiated recipients. In this study we generate hematopoietic-restricted models of Ptpn11E76K-mediated disease using Csf1r-MCM and Flt3Cre. We show that these animals have indolent MPN progression despite robust GM-CSF hypersensitivity and Ras-Erk hyperactivation. Rather, the dominant pathology is pronounced thrombocytopenia with expanded extramedullary hematopoiesis. Furthermore, we demonstrate that the timing of tamoxifen administration in Csf1r-MCM mice can specifically induce recombinase activity in either fetal or adult hematopoietic progenitors. We take advantage of this technique to show more rapid monocytosis following Ptpn11E76K expression in fetal progenitors compared with adult progenitors. Finally, we demonstrate that Ptpn11E76K results in the progressive reduction of T cells, most notably of CD4+ and naïve T cells. This corresponds to an increased frequency of T cell progenitors in the thymus and may help explain the occasional emergence of T-cell leukemias in JMML patients. Overall, our study is the first to describe the consequences of hematopoietic-restricted Ptpn11E76K expression in the absence of irradiation. Our techniques can be readily adapted by other researchers studying somatically-acquired blood disorders.

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Section: Discussionmentioning

confidence: 99%

Hematopoietic-restricted Ptpn11E76K reveals indolent MPN progression in mice

Tarnawsky

Wang

et al. 2018

Oncotarget

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“…The treatment plan for AML with T-LBL is still being researched (Table 1). [14][15][16] In the present case, the IA regimen was introduced as the initial treatment. Bone marrow findings improved, but the lymph nodes did not shrink.…”

Section: Discussionmentioning

confidence: 99%

Acute myeloid leukemia with T lymphoblastic lymphoma: a case report and literature review

et al. 2021

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Acute myeloid leukemia (AML) with T lymphoblastic lymphoma (T-LBL) is a hematologic tumor of two origins, myeloid and lymphoblastic, and is relatively rare in the same patient. We report a rare case of AML with T-LBL. After the patient was diagnosed, he received standard chemotherapy, which decreased the primitive bone marrow cell percentage from 84% to 5%; however, the enlarged superficial lymph nodes showed no obvious change in size. Immunohistochemistry revealed the following: cluster of differentiation (CD)3 (+), CD5 (+), CD7 (+), transmission disequilibrium test (TDT) (+), myeloperoxidase (MPO) (−), and lysozyme (Lys) (−). The lymph node morphology and immunohistochemical results indicated T-LBL. Therefore, the final diagnosis was AML with T-LBL, with both diseases occurring independently and concurrently.

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“…While the NRAS Q61R mutation has not been reported in JMML, two NRAS codon 61 mutations, specifically Q61H and Q61K, were recently described . There is one reported case of a patient with concurrent JMML and T‐lymphoblastic lymphoma . Interestingly, this patient had a shared missense NRAS mutation (G12C) in both the BM and lymph node, and he was successfully treated with allogeneic stem cell transplantation …”

Section: Discussionmentioning

confidence: 99%

“…There is one reported case of a patient with concurrent JMML and T‐lymphoblastic lymphoma . Interestingly, this patient had a shared missense NRAS mutation (G12C) in both the BM and lymph node, and he was successfully treated with allogeneic stem cell transplantation …”

Section: Discussionmentioning

confidence: 99%

Early T‐Cell Precursor Acute Lymphoblastic Leukemia in an Infant With an NRAS Q61R Mutation and Clinical Features of Juvenile Myelomonocytic Leukemia

Raikar

Scarborough

Sabnis

et al. 2016

Pediatric Blood & Cancer

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Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a subtype of T-acute lymphoblastic leukemia (T-ALL) arising from a primitive precursor. We present a unique case of an infant with ETP-ALL with a missense NRAS mutation in codon 61 (c.182A>G, p.Q61R). The patient also had a minor population of non-ETP T-ALL blasts and clinical features typically associated with juvenile myelomonocytic leukemia (JMML), namely, absolute monocytosis, splenomegaly, and elevated hemoglobin F. The treatment was initiated with chemotherapy, followed by cord blood transplantation. The patient achieved remission, but unfortunately died from transplant-related complications. This case highlights an NRAS mutation in ETP-ALL with JMML-like phenotype.

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Concurrent juvenile myelomonocytic leukemia and T‐lymphoblastic lymphoma with a shared missense mutation in NRAS

Cited by 7 publications

References 17 publications

Hematopoietic-restricted Ptpn11E76K reveals indolent MPN progression in mice

Hematopoietic-restricted Ptpn11E76K reveals indolent MPN progression in mice

Acute myeloid leukemia with T lymphoblastic lymphoma: a case report and literature review

Early T‐Cell Precursor Acute Lymphoblastic Leukemia in an Infant With an NRAS Q61R Mutation and Clinical Features of Juvenile Myelomonocytic Leukemia

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