RESUMO
Traditionally, skin involvement in chronic myelomonocytic leukemia (CMML) has been considered to be either specific (leukemia cutis) or non-specific, with granulomatous dermatitis included in the latter group. More recently, the true nature of the myeloid cells present in the cutaneous infiltrates of this theoretically reactive dermatitis is being clarified with the use of new molecular techniques such as next-generation sequencing. The same mutations in bone marrow (BM) myeloid neoplastic cells and in the cells of cutaneous infiltrates have been found. We present the case of a 77-year-old man who presented with spread and treatment-resistant skin granulomatous lesions previous to the diagnosis of CMML. The same clonal mutations in SRSF2, IDH1, and RUNX1 were found in both skin and BM with resolution of the lesions after the initiation of azacytidine. In conclusion, we report an exceptional case in which specific granulomatous cutaneous lesions have preceded and allowed the earlier diagnosis of an underlying CMML and a review of all previous similar cases in the literature, including molecular alterations.
Assuntos
Dermatite , Leucemia Mielomonocítica Crônica , Humanos , Masculino , Leucemia Mielomonocítica Crônica/patologia , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/complicações , Idoso , Dermatite/patologia , Granuloma/patologia , Fatores de Processamento de Serina-Arginina/genética , Mutação , Azacitidina/uso terapêutico , Isocitrato Desidrogenase , Subunidade alfa 2 de Fator de Ligação ao CoreRESUMO
RAS pathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression after hypomethylating agent (HMA) therapy, the current standard of care for the disease. Here, using single-cell, multi-omics technologies, we seek to dissect the biological mechanisms underlying the initiation and progression of RAS pathway-mutated CMML. We identify that RAS pathway mutations induce transcriptional reprogramming of hematopoietic stem and progenitor cells (HSPCs) and downstream monocytic populations in response to cell-intrinsic and -extrinsic inflammatory signaling that also impair the functions of immune cells. HSPCs expand at disease progression after therapy with HMA or the BCL2 inhibitor venetoclax and rely on the NF-κB pathway effector MCL1 to maintain survival. Our study has implications for the development of therapies to improve the survival of patients with RAS pathway-mutated CMML.
Assuntos
Apoptose , Leucemia Mielomonocítica Crônica , Mutação , Proteína de Sequência 1 de Leucemia de Células Mieloides , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Leucemia Mielomonocítica Crônica/patologia , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Humanos , Apoptose/efeitos dos fármacos , Animais , Mutação/genética , Camundongos , Transdução de Sinais/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/efeitos dos fármacos , Progressão da Doença , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , NF-kappa B/metabolismo , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Crise Blástica/patologia , Crise Blástica/tratamento farmacológico , Crise Blástica/genética , Crise Blástica/metabolismoRESUMO
Ten-eleven translocation 2 (TET2) plays a pivotal role in epigenetic regulation, cell differentiation, and the inflammatory response. It also mediates the transcriptional regulation for inflammatory cytokines, particularly interleukin-6. While loss-of-function mutation in TET2 has been associated with hematological malignancies, it has been increasingly recognized to cause atherosclerotic disease. The increased atherogenicity is thought to be the result of increased production of pro-inflammatory interleukin-1ß cytokines following activation of NLRP3 inflammasomes. We present a unique case of recurrent atherothrombosis in an elderly man who was diagnosed with chronic myelomonocytic leukemia in the setting of TET2 mutation.