Myelodysplastic syndrome with clonal karyotype evolution associated with trisomy 8 and ASXL1 mutation in well‐controlled HIV patient: Case report and literature review

To the Editor Nonspecific myelodysplastic features (MDF) due to hematopoietic effects of the human immunodeficiency virus (HIV) were frequent before the antiretroviral therapy (ART) era. Pronounced hypocellularity, plasmacytosis, and eosinophilia were observed and are referred to as HIVmyelopathy [1,2]. TheseMDF alterations generally resolve with the institution of ART. They should be separated from myelodysplastic syndrome (MDS), a heterogeneous groupofmyeloid clonal diseases. Myelodysplastic syndromes can have a primary cause, also called de novo MDS, or secondary (sMDS), both with the risk of progression to acutemyeloid leukemia (AML). Some case reports and small case series of MDS in well-controlled HIV patients were described [3-6]. Herein, a new case of a long-stand well-controlled HIV infected patient with MDS is reported. The MDS status evolved with clonal karyotype associated with trisomy 8 and ASXL1mutation. A 61-year-old black woman was diagnosed with HIV in 2002, and ART—Zidovudine, Lamivudine (3TC), and Efavirenz—was initiated. She remained on this treatment for 16 years with long-term suppressed viral load, and CD4 cell counts >600 cells/mm3. In January 2018, she presented with progressive anemia and mental depression and the scheme was switched to Tenofovir, 3TC, and Dolutegravir. In September 2018, she developed severe anemia and thrombocytopenia (hemoglobin [Hb] 4.3 g/dL, leucocyte 8.7 × 109/L, neutrophils 2.2 × 109/L, and platelets 45 × 109/L, reticulocyte 0.13%, and serum ferritin 1225 μg/L) with red blood cell transfusion dependency. The polymerase chain reaction for Parvovirus B19 was negative on the blood sample. Bone marrow (BM) aspiration and biopsy were performed. The morphology disclosed a BM hypercellular with multilineage dysplasia (80%) and blast cells (5%). The histology was characterized by erythroid reduction and granulocytic hyperplasia with increased precursor cells and abnormal localization of immature precursors (ALIP). No acid-fast or fungal microorganisms were observed. The G-banding of BM cells identified the karyotype: 47,XX,+8[5]/46,XX[9] (Figure 1A), and the fluorescence in situ hybridization (FISH) analysis confirmed the trisomy 8 (Figure 1B). ASXL1 andDNMT3A somatic mutations were tested by Sanger sequencing [7,8]. DNMT3A was wild type, and ASXL1mutation in exon

Myelodysplastic syndrome with clonal karyotype evolution associated with trisomy 8 and ASXL1 mutation in well-controlled HIV patient: Case report and literature review To the Editor Nonspecific myelodysplastic features (MDF) due to hematopoietic effects of the human immunodeficiency virus (HIV) were frequent before the antiretroviral therapy (ART) era. Pronounced hypocellularity, plasmacytosis, and eosinophilia were observed and are referred to as HIV myelopathy [1,2]. These MDF alterations generally resolve with the institution of ART. They should be separated from myelodysplastic syndrome (MDS), a heterogeneous group of myeloid clonal diseases.
Myelodysplastic syndromes can have a primary cause, also called de novo MDS, or secondary (sMDS), both with the risk of progression to acute myeloid leukemia (AML). Some case reports and small case series of MDS in well-controlled HIV patients were described [3][4][5][6]. Herein, a new case of a long-stand well-controlled HIV infected patient with MDS is reported. The MDS status evolved with clonal karyotype associated with trisomy 8 and ASXL1 mutation.
A 61-year-old black woman was diagnosed with HIV in 2002, and ART-Zidovudine, Lamivudine (3TC), and Efavirenz-was initiated. She remained on this treatment for 16 years with long-term suppressed viral load, and CD4 cell counts >600 cells/mm 3 . In January 2018, she presented with progressive anemia and mental depression and the scheme was switched to Tenofovir, 3TC, and Dolutegravir. In September 2018, she developed severe anemia and thrombocytopenia (hemoglobin [Hb] 4.3 g/dL, leucocyte 8.7 × 10 9 /L, neutrophils 2.2 × 10 9 /L, and platelets 45 × 10 9 /L, reticulocyte 0.13%, and serum ferritin 1225 g/L) with red blood cell transfusion dependency. The polymerase chain reaction for Parvovirus B19 was negative on the blood sample. Bone marrow (BM) aspiration and biopsy were performed. The morphology disclosed a BM hypercellular with multilineage dysplasia (80%) and blast cells (5%).  ( Figure 1D). FISH analysis using the probe LSI RUNX1 break apart (RUNX1 21q22 spectrum green/RUNX1T1 8q21 spectrum orange) identified cells with both trisomy 8 and trisomy 21 ( Figure 1E). BM analysis maintained the MDS-EB-1 pattern, showing a pleomorphic and hyperplastic bone marrow, absence of megakaryocytic sector, erythroid aplasia, hyperplasia myeloid with dysplasia, and 5% of blasts.
The biopsy of bone marrow depicted ALIP and erythroid aplasia.
A broad scientific review disclosed that only 23 cases of wellcontrolled HIV patients with MDS were described (Table 1) aging leading the acquisition of somatic mutations followed by clonal hematopoiesis [6]. Besides, ART is related to genotoxic effects [11] with genomic instability and loss of heterozygosity [12]. Other previous studies also linked ART to hematopoietic precursor cell dysplastic abnormalities [1,13,14]. We hypothesized that the coexistence of trisomy 8 and ASXL1 mutation in our patient would be a consequence of long-standing exposition to ART, leading to a sMDS. Mutations in ASXL1 are detected in 11-14% of MDS; most of them occur as heterozygous exon 12 frameshift or nonsense mutations and predict inferior prognosis [15]. Isolated trisomy 8 is found in about 7% of MDS cases and is considered a secondary or late event in the MDS evolution [15].
The chromosomes are frequently missegregated during mitosis in cancer cells. This process is known as whole-chromosome instability (W-CIN) and leads to aneuploidy. W-CIN induces tumorigenesis and treatment resistance. The mitotic stress associated with W-CIN is generally induced by oncogenes and suppressor tumor genes rather than mutations in genes involved in chromosome segregation [16]. Our Often, these patients are not eligible for hematopoietic stem cell transplantation due to their poor clinical condition [6]. Because of the lack of specific treatment for HIV/MDS patients, it is essential to unveil the mechanisms involved in its pathogenesis to led promissory therapy.

ACKNOWLEDGMENTS
The authors thank the patient who made samples available.

CONFLICT OF INTEREST
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
The documentation is available on a reasonable request to the corresponding author.