-
Cancers Nov 2023Leukemia cutis (LC) is defined as the leukemic infiltration of the epidermis, the dermis, and the subcutaneous tissue. Leukemia cutis may follow or occur simultaneously... (Review)
Review
Leukemia cutis (LC) is defined as the leukemic infiltration of the epidermis, the dermis, and the subcutaneous tissue. Leukemia cutis may follow or occur simultaneously with the diagnosis of systemic leukemia. However, cutaneous lesions are occasionally diagnosed as the primary manifestation of leukemia. Leukemic skin infiltrations demonstrate considerable variation regarding a number of changes, distribution, and morphology. The highest incidence of LC is observed in chronic lymphocytic leukemia, monocytic and myelomonocytic acute myeloid leukemia, and T-cell lineage leukemia. Although the pathogenic mechanism of the invasion of leukemic cells into the skin is not well understood, chemokine receptors and adhesion molecules as well as the genetic characteristics of leukemia are thought to play a role. Leukemic skin lesions may be localized or disseminated and may occur alone or in combination on any site of the skin, most frequently in the trunk and extremities. The most common clinical presentations of leukemia cutis are papules, nodules, macules, plaques, and ulcers. In most patients, the complete or partial resolution of cutaneous infiltrations occurs simultaneously with hematologic remission. However, in patients with resistant disease or recurrent skin infiltration, local radiotherapy can be used. This review presents recent data on the pathogenesis, diagnosis, and treatment of leukemic skin involvement in different types of leukemia.
PubMed: 38001655
DOI: 10.3390/cancers15225393 -
Haematologica Nov 2023Juvenile myelomonocytic leukemia (JMML) is a rare, generally aggressive myeloproliferative neoplasm affecting young children. It is characterized by granulomonocytic...
Juvenile myelomonocytic leukemia (JMML) is a rare, generally aggressive myeloproliferative neoplasm affecting young children. It is characterized by granulomonocytic expansion, with monocytosis infiltrating peripheral tissues. JMML is initiated by mutations upregulating RAS signaling. Approximately 10% of cases remain without an identified driver event. Exome sequencing of 2 unrelated cases of familial JMML of unknown genetics and analysis of the French JMML cohort identified 11 patients with variants in SH2B3, encoding LNK, a negative regulator of the JAK-STAT pathway. All variants were absent from healthy population databases, and mutation spectrum was consistent with a loss of function of the LNK protein. A stoploss variant was shown to affect both protein synthesis and stability. The other variants were either truncating or missense, the latter affecting the SH2 domain that interacts with activated JAK. Of the 11 patients, 8 from 5 families inherited pathogenic bi-allelic SH2B3 germline variants from their unaffected heterozygous parents. These children represent half of the cases with no identified causal mutation in the French cohort. They displayed typical clinical and hematological JMML features with neonatal onset and marked thrombocytopenia. They were characterized by absence of additional genetic alterations and a hypomethylated DNA profile with fetal characteristics. All patients showed partial or complete spontaneous clinical resolution. However, progression to thrombocythemia and immunity-related pathologies may be of concern later in life. Bi-allelic SH2B3 germline mutations thus define a new condition predisposing to a JMML-like disorder, suggesting that the JAK pathway deregulation is capable of initiating JMML, and opening new therapeutic options.
PubMed: 37981895
DOI: 10.3324/haematol.2023.283917 -
Oncology Reports Jan 2024U2 small nuclear RNA auxiliary factor 1 (U2AF1) is a multifunctional protein that plays a crucial role in the regulation of RNA splicing during eukaryotic gene... (Review)
Review
U2 small nuclear RNA auxiliary factor 1 (U2AF1) is a multifunctional protein that plays a crucial role in the regulation of RNA splicing during eukaryotic gene expression. U2AF1 belongs to the SR family of splicing factors and is involved in the removal of introns from mRNAs and exon-exon binding. Mutations in U2AF1 are frequently observed in myelodysplastic syndrome, primary myelofibrosis, chronic myelomonocytic leukaemia, hairy cell leukaemia and other solid tumours, particularly in lung, pancreatic, and ovarian carcinomas. Therefore, targeting U2AF1 for therapeutic interventions may be a viable strategy for treating malignant diseases. In the present review, the pathogenic mechanisms associated with U2AF1 in different malignant diseases were summarized, and the potential of related targeting agents was discussed. Additionally, the feasibility of natural product-based therapies directed against U2AF1 was explored.
Topics: Humans; Splicing Factor U2AF; RNA Splicing Factors; Neoplasms; RNA Splicing; Mutation
PubMed: 37975232
DOI: 10.3892/or.2023.8664 -
Cancers Oct 2023Juvenile myelomonocytic leukemia (JMML) is a deadly pediatric leukemia driven by pathway mutations, of which >35% are gain-of-function in . Although DNA...
Juvenile myelomonocytic leukemia (JMML) is a deadly pediatric leukemia driven by pathway mutations, of which >35% are gain-of-function in . Although DNA hypermethylation portends severe clinical phenotypes, the landscape of histone modifications and chromatin profiles in JMML patient cells have not been explored. Using global mass cytometry, Epigenetic Time of Flight (EpiTOF), we analyzed hematopoietic stem and progenitor cells (HSPCs) from five JMML patients with mutations. These data revealed statistically significant changes in histone methylation, phosphorylation, and acetylation marks that were unique to JMML HSPCs when compared with healthy controls. Consistent with these data, assay for transposase-accessible chromatin with sequencing (ATAC-seq) analysis revealed significant alterations in chromatin profiles at loci encoding post-translational modification enzymes, strongly suggesting their mis-regulated expression. Collectively, this study reveals histone modification pathways as an additional epigenetic abnormality in JMML patient HSPCs, thereby uncovering a new family of potential druggable targets for the treatment of JMML.
PubMed: 37958378
DOI: 10.3390/cancers15215204 -
Leukemia Jan 2024Juvenile myelomonocytic leukemia (JMML) is an aggressive hematopoietic disorder of infancy and early childhood driven by constitutively active RAS signaling and...
Juvenile myelomonocytic leukemia (JMML) is an aggressive hematopoietic disorder of infancy and early childhood driven by constitutively active RAS signaling and characterized by abnormal proliferation of the granulocytic-monocytic blood cell lineage. Most JMML patients require hematopoietic stem cell transplantation for cure, but the risk of relapse is high for some JMML subtypes. Azacitidine was shown to effectively reduce leukemic burden in a subset of JMML patients. However, variable response rates to azacitidine and the risk of drug resistance highlight the need for novel therapeutic approaches. Since RAS signaling is known to interfere with the intrinsic apoptosis pathway, we combined various BH3 mimetic drugs with azacitidine in our previously established patient-derived xenograft model. We demonstrate that JMML cells require both MCL-1 and BCL-X for survival, and that these proteins can be effectively targeted by azacitidine and BH3 mimetic combination treatment. In vivo azacitidine acts via downregulation of antiapoptotic MCL-1 and upregulation of proapoptotic BH3-only. The combination of azacitidine with BCL-X inhibition was superior to BCL-2 inhibition in eliminating JMML cells. Our findings emphasize the need to develop clinically applicable MCL-1 or BCL-X inhibitors in order to enable novel combination therapies in JMML refractory to standard therapy.
Topics: Humans; Child, Preschool; Azacitidine; Leukemia, Myelomonocytic, Juvenile; Myeloid Cell Leukemia Sequence 1 Protein; bcl-X Protein; Apoptosis; Cell Line, Tumor
PubMed: 37945692
DOI: 10.1038/s41375-023-02079-5 -
JCO Precision Oncology Sep 2023Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric malignancy with myelodysplastic and myeloproliferative features. Curative treatment is restricted to...
PURPOSE
Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric malignancy with myelodysplastic and myeloproliferative features. Curative treatment is restricted to hematopoietic stem-cell transplantation. Fludarabine combined with cytarabine (FLA) and 5-azacitidine (AZA) monotherapy are commonly used pre-transplant therapies. Here, we present a drug screening strategy using a flow cytometry-based precision medicine platform to identify potential additional therapeutic vulnerabilities.
METHODS
We screened 120 dual- and 10 triple-drug combinations (DCs) on peripheral blood (n = 21) or bone marrow (n = 6) samples from 27 children with JMML to identify DCs more effectively reducing leukemic cells than the DCs' components on their own. If fewer leukemic cells survived a DC ex vivo treatment compared with that DC's most effective component alone, the drug effect was referred to as cooperative. The difference between the two resistant fractions is the effect size.
RESULTS
We identified 26 dual- and one triple-DC more effective than their components. The differentiation agent tretinoin (TRET; all-trans retinoic acid) reduced the resistant fraction of FLA in 19/21 (90%) samples (decrease from 15% [2%-61%] to 11% [2%-50%] with a mean effect size of 3.8% [0.5%-11%]), and of AZA in 19/25 (76%) samples (decrease from 69% [34%-100+%] to 47% [17%-83%] with a mean effect size of 16% [0.3%-40%]). Among the resistant fractions, the mean proportion of CD38 cells increased from 7% (0.03%-25%; FLA) to 17% (0.3%-38%; FLA + TRET) or from 10% (0.2%-31%; AZA) to 51% (0.8%-88%; AZA + TRET).
CONCLUSION
TRET enhanced the effects of FLA and AZA in ex vivo assays with primary JMML samples.
Topics: Child; Humans; Leukemia, Myelomonocytic, Juvenile; Tretinoin; Azacitidine; Hematopoietic Stem Cell Transplantation
PubMed: 37944074
DOI: 10.1200/PO.23.00302 -
AME Case Reports 2023Chronic myelomonocytic leukemia (CMML) is a rare, malignant, clonal hematopoietic disorder with features of both myelodysplastic syndrome (MDS) and myeloproliferative...
BACKGROUND
Chronic myelomonocytic leukemia (CMML) is a rare, malignant, clonal hematopoietic disorder with features of both myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). It is classified as MDS/MPN overlap syndrome by the World Health Organization (WHO), and the prognosis is generally poor. Solid tumors are rarely associated with or are secondary to CMML.
CASE DESCRIPTION
We here reported a case of a 75-year-old female patient with persistent peripheral blood monocytosis and bone marrow blasts ≤20%. A diagnosis of CMML was made. Unexpectedly, she presented with recurrent melena and red blood cell (RBC) transfusions were ineffective. Capsule endoscopy revealed gastric space-occupying lesions, and pathological biopsy confirmed gastric adenocarcinoma. Because of the patient's history of coronary heart disease and the fact that she underwent percutaneous coronary intervention with stenting less than half a year ago, the diagnosis and treatment of this patient required a multidisciplinary team of hematologists, oncologists, anesthesiologists and cardiologists.
CONCLUSIONS
Physicians should consider the possibility of other malignant solid tumors in patients with CMML. For patients at high risk for gastrointestinal endoscopy, capsule endoscopy may be a safer way to determine if a patient needs further endoscopic biopsy. There are currently no guidelines for the treatment of CMML with gastric cancer.
PubMed: 37942038
DOI: 10.21037/acr-23-12 -
Cancer Medicine Dec 2023The clinical significance of protein tyrosine phosphatase nonreceptor type 11 mutation (PTPN11 ) in acute myeloid leukemia (AML) is underestimated.
BACKGROUND
The clinical significance of protein tyrosine phosphatase nonreceptor type 11 mutation (PTPN11 ) in acute myeloid leukemia (AML) is underestimated.
METHODS
We collected the data of AML patients with mutated PTPN11 and wild-type PTPN11 (PTPN11 ) treated at our hospital and analyzed their clinical characteristics and prognosis.
RESULTS
Fifty-nine PTPN11 and 124 PTPN11 AML patients were included. PTPN11 was more common in myelomonocytic and monocytic leukemia, and was more likely to co-mutate with KRAS, KMT2C, NRAS, U2AF1, NOTCH1, IKZF1, and USH2A mutations than PTPN11 . The overall survival for AML patients with PTPN11 was significantly shorter than that for those with PTPN11 (p = 0.03). The negative impact of PTPN11 on overall survival was pronounced in the "favorable" and "intermediate" groups of ELN2017 risk stratification, as well as in the wild-type NPM1 group (p = 0.01, p = 0.01, and p = 0.04).
CONCLUSION
PTPN11 is associated with distinct clinical and molecular characteristics, and adverse prognosis in AML patients.
Topics: Adult; Humans; Prognosis; Nucleophosmin; Leukemia, Myeloid, Acute; Mutation; China; Protein Tyrosine Phosphatase, Non-Receptor Type 11
PubMed: 37937729
DOI: 10.1002/cam4.6669 -
Medicine Oct 2023The rare t(3;21)(q26;q22) translocation results in gene fusion and generates multiple fusion transcripts, which are typically associated with therapy-related...
RATIONALE
The rare t(3;21)(q26;q22) translocation results in gene fusion and generates multiple fusion transcripts, which are typically associated with therapy-related myelodysplastic syndrome, acute myeloid leukemia, and chronic myelogenous leukemia. Here, we report a rare case of de novo acute myelomonocytic leukemia in a young child with t(3;21)(q26;q22).
PATIENT CONCERNS
A 2-and-a-half-year-old female patient presented with abdominal pain, cough, paleness, and fever for 3 weeks, without any history of malignant diseases.
DIAGNOSES
Chest computed tomography revealed pneumonia. Bone marrow smear confirmed acute myelomonocytic leukemia. Cytogenetic analysis and Sanger sequencing identified RUNX1-MECOM and RUNX1-RPL22 fusion genes as a result of t(3;21)(q26;q22).
INTERVENTIONS
The patient received 3 courses of chemotherapy, but bone marrow smear examination showed no remission. According to the wishes of the patient family, the allogeneic hematopoietic stem cell transplantation (Allo-HSCT) was chosen.
OUTCOMES
The patient did not experience any adverse reactions after Allo-HSCT. The red blood cells and platelets increased without transfusion. The pneumonia recovered after antibiotic treatment.
LESSONS
The patient recovered well after Allo-HSCT. Therefore, for patients with RUNX1-MECOM and RUNX1-RPL22 fusion genes, transplantation may be a good choice when chemotherapy is not effective.
Topics: Female; Humans; Child; Child, Preschool; Core Binding Factor Alpha 2 Subunit; Leukemia, Myelomonocytic, Acute; Leukemia, Myeloid, Acute; Hematopoietic Stem Cell Transplantation; Translocation, Genetic; Pneumonia; Chromosomes, Human, Pair 21
PubMed: 37904382
DOI: 10.1097/MD.0000000000035721