Abstract
Simple SummaryB-cell acute lymphoblastic leukemia (B-ALL) is characterized by an uncontrolled proliferation of blood cells in the bone marrow. A small fraction of B-ALL patients shows abnormally low chromosome numbers, defined as hypodiploidy, in leukemic cells. Hypodiploidy with less than 40 chromosomes is a rare genetic abnormality in B-ALL and is associated to an extremely poor outcome, with low survival rates both in pediatric and adult cases. In this review, we describe the main clinical and genetic features of hypodiploid B-ALL subtypes with less than 40 chromosomes, the current treatment protocols and their clinical outcomes. Additionally, we discuss the potential cellular mechanisms involved on the origin of hypodiploidy, as well as its leukemogenic impact. Studies aiming to decipher the biological mechanisms involved in hypodiploid subtypes of B-ALL with less than 40 chromosomes are crucial to improve the poor survival rates in these patients. Hypodiploidy with less than 40 chromosomes is a rare genetic abnormality in B-cell acute lymphoblastic leukemia (B-ALL). This condition can be classified based on modal chromosome number as low-hypodiploidy (30–39 chromosomes) and near-haploidy (24–29 chromosomes), with unique cytogenetic and mutational landscapes. Hypodiploid B-ALL with <40 chromosomes has an extremely poor outcome, with 5-year overall survival rates below 50% and 20% in childhood and adult B-ALL, respectively. Accordingly, this genetic feature represents an adverse prognostic factor in B-ALL and is associated with early relapse and therapy refractoriness. Notably, half of all patients with hypodiploid B-ALL with <40 chromosomes cases ultimately exhibit chromosome doubling of the hypodiploid clone, resulting in clones with 50–78 chromosomes. Doubled clones are often the major clones at diagnosis, leading to “masked hypodiploidy”, which is clinically challenging as patients can be erroneously classified as hyperdiploid B-ALL. Here, we summarize the main cytogenetic and molecular features of hypodiploid B-ALL subtypes, and provide a brief overview of the diagnostic methods, standard-of-care treatments and overall clinical outcome. Finally, we discuss molecular mechanisms that may underlie the origin and leukemogenic impact of hypodiploidy and may open new therapeutic avenues to improve survival rates in these patients.
Highlights
Acute lymphoblastic leukemia (ALL) is a neoplasm arising from lymphoid precursor cells and can be classified as B-cell precursor ALL (B-ALL) or T-ALL based on the immunophenotype of the neoplastic cells [1]
bone marrow (BM) and peripheral blood (PB) are involved in most cases, B-ALL occasionally presents with primary nodal or extranodal sites (B-lymphoblastic lymphoma), which predominantly affect skin, soft tissue, bone and lymph nodes [4]
There is only circumstantial evidence for the cellular mechanisms leading to hypodiploidy and its pathogenic consequences. Genomic analyses of these subtypes have been difficult given the limited number of cases; a study on a small cohort of 8 near-haploid and 4 low-hypodiploid B-ALL samples suggested that the massive loss of chromosomes is the primary oncogenic event, with other oncogenic insults occurring after hypodiploidy [37]
Summary
Acute lymphoblastic leukemia (ALL) is a neoplasm arising from lymphoid precursor cells and can be classified as B-ALL or T-ALL based on the immunophenotype of the neoplastic cells [1]. The disease is characterized by the uncontrolled proliferation of leukemic cells, which invade the bone marrow (BM), peripheral blood (PB), and other hematopoietic tissues including spleen, liver, and lymph nodes, resulting in a hematopoietic displacement which is responsible for the cytopenias frequently observed at diagnosis. T-lymphoblastic leukemia/lymphoma Early T-cell precursor lymphoblastic leukemia. There are several known risk factors that can help to stratify patients with B-ALL, including adverse demographic factors such as age 50 × 109/L) [9]. Aneuploidy—defined as the gain or loss of one or more whole chromosomes—is an important prognostic factor [12], and will be examined in this review; the favorable risk of hyperdiploidy and the adverse risk of hypoploidy. One important risk factor with prognostic value is the response to treatment, evaluated as the detection of minimal residual disease (MRD) at specific timepoints of treatment [15]
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