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Subspecialties Hematology, Oncology, Genetics and epigenetics, Biochemistry and molecular biology

Zooming in on Hematopathology

Credit: Atlas of Pulmonary Pathology: Flickr

As we continue our exploration of the latest news in hematology and hematopathology, we’re moving away from our coverage of the high-level updates and advances to zoom in on a particular hematopathological subfield. In fact, we’re zooming in so far that we’ve entered the molecular level!

AML expansion pack
 

An expansion of the first proteogenomic characterization of acute myeloid leukemia bone marrow blasts has further detailed the data set with an additional 90 AML patient samples. The team responsible for the expansion were able to confirm the proteomic Mito-AML subtype, as well as poor outcomes following chemotherapy. They also shed light on NPM1mut AML’s proteomic landscape – ultimately identifying two subgroups characterized by either “myelomonocytic differentiation” or a “progenitor and stem cell-like blast state” (1).

Lay of the molecular land
 

An NGS study designed to detect pathogenic variants of common chronic lymphocytic leukemia gene mutations and their associations with IGHV mutational status and cytogenetic abnormalities has identified 96 different variants in 124 patients. A little over 50 percent of patients had at least one mutation, of which 62.5 percent were clonal. Thirty-six patients showed just one pathogenic variant, while 88 carried between two to four. The gene that saw the most frequent mutations was the NOTCH1, followed by TP53, SF3B1, FBXW7, and BRIC3. Those with mutated IGHV had mainly FBXW7 and BIRC3 mutations, with FBXW7 detected in seven percent of patients – a higher recording than previous studies (2).

A tale of two DLBCLs
 

Primary refractory diffuse large B-cell lymphoma (prDLBCL) is a form of DLBCL that progresses during treatment or fails to respond to immunochemotherapy. Although prognosis is poor, it is not currently possible to identify prDLBCL at initial diagnosis, prompting researchers to identify its molecular markers. Research revealed that prDLBCL makes up six percent of newly diagnosed cases and showed a high frequency of TP53 alterations and MYC copy increases in prDLBCL. The data suggest that TP53 and MYC alterations may play a role in treatment resistance and could be an important indicator of poor patient outcomes (3).

Taking the MYC
 

Samples from 1,806 patients with AML were retrospectively interrogated with NGS techniques or a PCR-based MYC-ITD assay. MYC abnormalities were identified in 58 patients, with half having MYC-ITD, 46.5 percent a SNV or indel, and 3.5 percent both MYC-ITD and a SNV. The team also showed a high prevalence of co-occurring core-binding factor fusions with MYC-ITD and high occurrence of simultaneous NUP98-NSD1, FLT3-ITD, and NPM1 mutations in MYC SNV/indel. Patients with MYC-ITD have better clinical outcomes, but those with SNVs/indels have clinical outcomes similar to high-risk patients – likely due to co-occurrence with disease-associated fusions (4).

Rare disorder revelations
 

An investigation into the molecular mechanisms of histiocytic and dendritic cell disorders has revealed a 41 percent prevalence of mutations in epigenetic genes – highlighting further mechanisms of disease pathogenesis. The mutations were specifically enriched in tumors with non-BRAF V600E mutations, and in multicentric reticulohistiocytosis and malignant histiocytosis. The most common epigenetic mutations were in KMT2C (34 percent), KMT2D (23 percent), and ARID1A (19 percent) (5).

Inflammatory observations
 

Serum protein profiling in relation to large B-cell lymphomas (LBCL) has highlighted a novel interaction between lymphomas and body host – where tissue inflammation extends beyond ctDNA characteristics and is associated with patient response, TME features, and poor patient outcomes. When researchers integrated serum protein and plasma ctDNA profiling, they were able to establish new associations that widen the potential of liquid biopsies in LBCL cases (6).

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  1. S Wolf et al., “Proteomic Characterization of Acute Myeloid Leukemia.” Presented at the 64th ASH Annual Meeting and Exposition; December 10, 2022; New Orleans, USA. Abstract #1500.
  2. A Mosolygo-Lukacs et al., “Molecular Landscape of Chronic Lymphocytic Leukemia Using Targeted Gene Panel Sequencing.” Presented at the 64th ASH Annual Meeting and Exposition; December 10, 2022; New Orleans, USA. Abstract #2183.
  3. AM Bock et al., “Molecular Landscape of Primary Refractory DLBCL.” Presented at the 64th ASH Annual Meeting and Exposition; December 10, 2022; New Orleans, USA. Abstract #4156.
  4. DC Kirkey et al., “Clinical and Functional Implications of MYC Variants As a New Class of Pathogenic Variants in AML.” Presented at the 64th ASH Annual Meeting and Exposition; December 10, 2022; New Orleans, USA. Abstract #1472.
  5. G Goyal et al., “High Prevalence of Epigenetic Mutations in Histiocytic and Dendritic Cell Disorders: Results from Molecular Analysis of a Large Cohort from Histiocytosis Working Group.” Presented at the 64th ASH Annual Meeting and Exposition; December 10, 2022; New Orleans, USA. Abstract #13.
  6. M Arffman., “ Serum Proteome Profiling Reveals Inflammatory, Molecular and Prognostic Information Beyond the Ctdna in Aggressive B-Cell Lymphomas.” Presented at the 64th ASH Annual Meeting and Exposition; December 10, 2022; New Orleans, USA. Abstract #548.
About the Author
George Francis Lee

Associate Editor, The Pathologist

Like most people, I didn’t know exactly what I wanted to do after university. But one thing was certain – writing would play a central role. Not one to walk the path most traveled, I decided to spend my next few years freelancing to hone my skills as a writer and further cement my love for language. Reaching people through writing is important to me and I look forward to connecting with thousands of people through Texere’s passionate audience.

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