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Rarely, atypical cyclin D1\u2010negative MCL and in situ MCL neoplasia are identified. Prognostication of MCL is further refined by identifying somatic mutations (such as\n                    <jats:italic>TP53<\/jats:italic>\n                    ,\n                    <jats:italic>NSD2<\/jats:italic>\n                    ,\n                    <jats:italic>KMT2D<\/jats:italic>\n                    ), methylation status, chromatin organization pattern, SOX\u201011 expression, minimal residual disease (MRD), and genomic clusters. Lymphoid tissue microenvironment studies demonstrated the role of B\u2010cell receptor signaling, nuclear factor kappa B (NF\u2010kB), colony\u2010stimulating factor (CSF)\u20101, the CD70\u2010SOX\u201011 axis. Molecular mechanism of resistance, mutation dynamics, and pathogenic pathways (B\u2010cell receptor (BCR), oxidative phosphorylation, and MYC) were identified in mediating resistance to various treatments (bruton tyrosine kinase (BTK) inhibitors [ibrutinib, acalabrutinib]. Treatment options range from conventional chemoimmunotherapy and stem cell transplantation (SCT) to targeted therapies against BTK (covalent and noncovalent), Bcl2, ROR1, cellular therapy such as anti\u2010CD19 chimeric antigen receptor therapy (CAR\u2010T), and most recently bispecific antibodies against CD19 and CD20. MCL patients frequently relapse. Complex pathogenesis and the management of patients with progression after treatment with BTK\/Bcl2 inhibitors and CAR\u2010T (triple\u2010resistant MCL) remain a challenge. Next\u2010generation clinical trials incorporating newer agents and concurrent translational and molecular investigations are ongoing.\n                  <\/jats:p>","DOI":"10.1002\/ajh.26523","type":"journal-article","created":{"date-parts":[[2022,3,10]],"date-time":"2022-03-10T07:07:11Z","timestamp":1646896031000},"page":"638-656","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":149,"title":["Mantle cell lymphoma in 2022\u2014A comprehensive update on molecular pathogenesis, risk stratification, clinical approach, and current and novel treatments"],"prefix":"10.1002","volume":"97","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2735-168X","authenticated-orcid":false,"given":"Preetesh","family":"Jain","sequence":"first","affiliation":[{"name":"Department of Lymphoma\/Myeloma. 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