Progression in Myeloid Neoplasms: Beyond the Myeloblast

Abstract

Disease progression in myelodysplastic syndromes (MDS), myelodysplastic-myeloproliferative neoplasms (MDS/MPN), and myeloproliferative neoplasms (MPN), altogether referred to as myeloid neoplasms (MN), is a major source of mortality. Apart from transformation to acute myeloid leukemia, the clinical progression of MN is mostly due to the overgrowth of pre-existing hematopoiesis by the MN without an additional transforming event. Still, MN may evolve along other recurrent yet less well-known scenarios: (1) acquisition of MPN features in MDS or (2) MDS features in MPN, (3) progressive myelofibrosis (MF), (4) acquisition of chronic myelomonocytic leukemia (CMML)-like characteristics in MPN or MDS, (5) development of myeloid sarcoma (MS), (6) lymphoblastic (LB) transformation, (7) histiocytic/dendritic outgrowths. These MN-transformation types exhibit a propensity for extramedullary sites (e.g., skin, lymph nodes, liver), highlighting the importance of lesional biopsies in diagnosis. Gain of distinct mutations/mutational patterns seems to be causative or at least accompanying several of the above-mentioned scenarios. MDS developing MPN features often acquire MPN driver mutations (usually JAK2), and MF. Conversely, MPN gaining MDS features develop, e.g., ASXL1, IDH1/2, SF3B1, and/or SRSF2 mutations. Mutations of RAS-genes are often detected in CMML-like MPN progression. MS ex MN is characterized by complex karyotypes, FLT3 and/or NPM1 mutations, and often monoblastic phenotype. MN with LB transformation is associated with secondary genetic events linked to lineage reprogramming leading to the deregulation of ETV6, IKZF1, PAX5, PU.1, and RUNX1. Finally, the acquisition of MAPK-pathway gene mutations may shape MN toward histiocytic differentiation. Awareness of all these less well-known MN-progression types is important to guide optimal individual patient management.

Clinical, Histopathological and Molecular Spectrum of Cutaneous Lesions in Myelodysplastic Syndrome and Myeloproliferative Neoplasms (MDS/MPN): An Integrative Review

“…Apart from transformation to AML and overgrowth of pre-existing hematopoiesis by the myeloid neoplasm without an additional transforming event, there are other recurrent less well-known scenarios that exhibit a propensity for extramedullary sites like the skin. These scenarios include: (1) acquisition of MDS features in MPN, (2) acquisition of MPN features in MDS, (3) progressive myelofibrosis (MF), ( 4) acquisition of CMML-like features, (5) development of granulocytic sarcoma/leukemia cutis, (6) lymphoblastic transformation, and ( 7) histiocytic and dendritic cell overgrowth [53]. Here, we are going to describe the cutaneous lesions more frequently found in MDS/MPN neoplasms with disease progression and how the gain of distinct mutations/mutational patterns seem to be responsible or at least concomitant with these clinical scenarios.…”

A retrospective case-control study for Clinical Validation of mutated ZNF208 as a novel biomarker of fatal blast crisis in Chronic Myeloid Leukemia

“…Our laboratory recently showed a novel transcription factor ZNF208 with a missense mutation (c.64G>A) associated with the progression of chronic myeloid leukemia (CML) [10]. Keeping in view that no reliable molecular biomarker is currently in clinical practice to early detect the CML patients at risk of developing fatal blast crisis and their timely therapeutic intervention in order to stop or delay their acute transformation [3, 5, 6], there was an urgent need to clinically validate this important finding in a broader population of patients with advanced-phase (AP) and blast crisis (BC) CML, using control-case studies [10]. Hence, the objective of this investigation was to clinically authenticate mutant ZNF208 as a new biomarker for the progression of chronic myeloid leukemia (CML).…”

“…Regrettably, certain individuals experience resistance to TKIs, resulting in therapy failure and progression to BC-CML [6]. However, the exact mechanisms responsible for the progression of CML are not fully understood, and there is a scarcity of reliable molecular markers for progression of CML to accelerated and blast crisis phases [3]. It makes early detection of CML patients at risk of disease progression, specifically to blast crisis, as one of biggest issues in 21 st century cancer medicine [5,6].…”

“…Our laboratory recently showed a novel transcription factor ZNF208 with a missense mutation (c.64G>A) associated with the progression of chronic myeloid leukemia (CML) [10]. Keeping in view that no reliable molecular biomarker is currently in clinical practice to early detect the CML patients at risk of developing fatal blast crisis and their timely therapeutic intervention in order to stop or delay their acute transformation [3,5,6] ,…”

Current Challenges in the Characterization of Myeloid Neoplasms

“…Drs. Faria and Tzankov provide a comprehensive analysis of the current knowledge and experience in disease evolution in myeloid neoplasms, including the rare and poorly understood phenomena of acquisition of MPN features in MDS and, vice versa, acquired MDS characteristics in MPN, development of persistent monocytosis in MDS/MPN, lymphoblastic and histiocytic/ dendritic transformation [9]. Detailed molecular analysis is provided to explain the current understanding of the phenotype-genotype associations.…”