• CMML o Diagnosis o Treatments o Molecular profile o Mutational landscape, Epigenetics factor (Tet2/ Ezh2), Signalling factors (NRas/CBL…), Splicing factors (SRSF2, SF3B1…) • SPLICING ABNORMALITIE

This literature review plan outlines the current understanding of chronic myelomonocytic leukemia (CMML) based on the provided evidence, focusing on diagnostic criteria, the molecular landscape of epigenetic and splicing mutations, and contemporary therapeutic strategies.

Summary

CMML is a complex myelodysplastic/myeloproliferative (MDS/MPN) overlap syndrome characterized by persistent monocytosis and a high frequency of somatic mutations in epigenetic regulators and splicing factors (Direct, High; PMID: 31559392). While hypomethylating agents (HMAs) provide palliative benefit, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative intervention (Direct, High; PMID: 31559392).

1. Diagnostic Framework and Classification

• WHO 2016 Criteria: Diagnosis requires persistent (>3 months) peripheral blood monocytosis (≥1 × 10⁹/L and ≥10% of the white blood cell differential) and the exclusion of other myeloid neoplasms like BCR-ABL1+ chronic myeloid leukemia (Direct, High; PMID: 31559392).
• Flow Cytometry: A characteristic increase in the classical monocyte fraction (MO1; CD14⁺/CD16⁻) to >94% of total monocytes serves as a highly specific and sensitive diagnostic marker.
• Morphological Subtyping: Patients are classified into CMML-0, -1, or -2 based on blast percentages in the blood and bone marrow, and further divided into myelodysplastic (MDS-CMML; WBC <13 × 10⁹/L) or myeloproliferative (MP-CMML; WBC ≥13 × 10⁹/L) subtypes (Direct, High; PMID: 31559392).

2. Molecular Profile and Mutational Landscape

• Epigenetic Regulators: TET2 is the most frequently altered gene (~60%), often occurring as an early clonal event that skews hematopoiesis toward the myeloid compartment (Direct, High; PMID: 31559392). ASXL1 mutations (~40%) are also prevalent and associated with poor prognosis in certain models (Direct, High; PMID: 31559392).
• Splicing Factors: SRSF2 mutations occur in approximately 50% of cases and are a hallmark of CMML molecular biology (Direct, High; PMID: 31559392).
• Signaling Pathways: NRAS alterations are particularly enriched in the MP-CMML subtype (Direct, High; PMID: 31559392). Studies in mouse models demonstrate that concurrent TET2/NRAS G12D alterations induce an aggressive phenotype by disrupting mitogen-activated protein (MAP) pathways (Direct, High; PMID: 31559392).
• Clonal Evolution and Resistance: EZH2 mutations have been identified in subclones emerging during HMA treatment, contributing to leukemic transformation (Direct, High; PMID: 31559392).

3. Therapeutic Strategies and Clinical Outcomes

• Approved Palliative Therapies: 5-azacitidine and decitabine (HMAs) improve survival and delay AML transformation but do not significantly reduce mutational allele burden, suggesting their action is primarily epigenetic rather than cytotoxic (Direct, High; PMID: 31559392).
• Investigational Targeted Agents:
  • Splicing Modulators: H3B-8800 is a small molecule currently under investigation for targeting splicing abnormalities (Direct, High; PMID: 31559392).
  • Kinase Inhibitors: Ruxolitinib (JAK1/2 inhibitor) has shown an overall response rate of 46% in patients, with significant symptom improvement in the MP-CMML subtype (Direct, High; PMID: 31559392).
  • Immunotherapy: SL-401 (targeting CD123) has shown activity in relapsed/refractory cases, and anti-GM-CSF antibodies (lenzilumab) are being explored (Direct, High; PMID: 31559392).
• Curative Intervention: Allogeneic HSCT is recommended for intermediate or high-risk disease in eligible patients, as it is the only treatment capable of providing long-term remission (Direct, High; PMID: 31559392).

4. Evidence Gaps in Current Literature

The provided context does not contain sufficient evidence to address the following components of the research plan:
* CHD8 Role: The molecular profile and role of CHD8 chromatin remodeling in CMML pathogenesis are not reported (Not reported; PMID: 31559392).
* CBL Signaling: While signaling pathways are mentioned generally, specific details regarding CBL mutational impacts are not provided in the text (Not reported; PMID: 31559392).
* DNA Damage/PARP Inhibitors: The context does not mention PARP inhibitors or specific therapeutic strategies targeting DNA damage pathways in CMML (Not reported; PMID: 31559392).

Additional literature searches are required to characterize the role of CHD8 and CBL in CMML and to evaluate the status of PARP inhibition in this disease.

What are the molecular mechanisms by which CHD8 and CBL mutations contribute to the pathogenesis of CMML?

How do PARP inhibitors and other DNA damage response-targeting agents perform in preclinical or clinical CMML trials?

What specific splicing abnormalities are targeted by H3B-8800 and how do they correlate with SRSF2 or SF3B1 mutational status?

Unverified Citations

The following sources failed to support their assigned claims after 3 verification rounds designed to ensure only high-confidence, relevant references are retained:

• PMID:31559392 — 6%) diagnostic marker
  Failed: conclusion — The claim is a fragment containing a percentage and 'diagnostic marker' without a clear subject or finding supported by the paper.